or structure: An update

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Contents lists available at SciVerse ScienceDirect

Journal of Dermatological Science journal homepage: www.elsevier.com/jds

Invited Review Article

Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update Motonobu Nakamura a,*, Marlon R. Schneider b, Ruth Schmidt-Ullrich c, Ralf Paus d,e a

Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany c Max-Delbru¨ck-Center, Berlin, Germany d Department of Dermatology, University of Luebeck, Luebeck, Germany e Institute of Inflammation and Repair, University of Manchester, Manchester, UK b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 30 August 2012 Received in revised form 2 October 2012 Accepted 4 October 2012

Human hair disorders comprise a number of different types of alopecia, atrichia, hypotrichosis, distinct hair shaft disorders as well as hirsutism and hypertrichosis. Their causes vary from genodermatoses (e.g. hypotrichoses) via immunological disorders (e.g. alopecia areata, autoimmune cicatrical alopecias) to hormone-dependent abnormalities (e.g. androgenetic alopecia). A large number of spontaneous mouse mutants and genetically engineered mice develop abnormalities in hair follicle morphogenesis, cycling, and/or hair shaft formation, whose analysis has proven invaluable to define the molecular regulation of hair growth, ranging from hair follicle development, and cycling to hair shaft formation and stem cell biology. Also, the accumulating reports on hair phenotypes of mouse strains provide important pointers to better understand the molecular mechanisms underlying human hair growth disorders. Since numerous new mouse mutants with a hair phenotype have been reported since the publication of our earlier review on this matter a decade ago, we present here an updated, tabulated mini-review. The updated annotated tables list a wide selection of mouse mutants with hair growth abnormalities, classified into four categories: Mutations that affect hair follicle (1) morphogenesis, (2) cycling, (3) structure, and (4) mutations that induce extrafollicular events (for example immune system defects) resulting in secondary hair growth abnormalities. This synthesis is intended to provide a useful source of reference when studying the molecular controls of hair follicle growth and differentiation, and whenever the hair phenotypes of a newly generated mouse mutant need to be compared with existing ones. ß 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: Hair follicle morphogenesis Hair cycle Knockout Mouse Transgenic

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis of hair follicle morphogenesis and cycling: the importance of professionally executed, quantitative histomorphometry Mouse models with spontaneous or randomly induced mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transgenic mice and choice of promoters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeted mutagenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selection and organisation of the presented mouse mutant tables. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Published hair phenotype descriptions: cautionary comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: ENU, ethyl-nitrosourea induced chemical mutagenesis; GEMs, genetically engineered mice; HF, hair follicle; Rad, radiation induced; S, spontaneous mutation; Tg, transgenic; TGF, transforming growth factor; Tm, targeted mutation. * Corresponding author at: Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Tel.: +81 93 691 7445; fax: +81 93 691 0907. E-mail address: [email protected] (M. Nakamura). 0923-1811/$36.00 ß 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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1. Introduction Over the past two decades, the molecular controls that drive hair follicle (HF) development and cycling have become one of the most intensively investigated and productive areas of skin research. Here, fundamentally important controls that range from mechanisms of organ induction and morphogenesis via principles of stem cell and pigmentation biology, topobiology, cell commitment, differentiation, and programmed death to complex cell-cell and tissue interactions can be studied exemplarily in a model miniorgan [1,2]. As such, the study of hair growth phenomena and of mutations associated with hair phenotype changes has permitted novel insights into general biological principles that extend far beyond skin and hair research. Moreover, the study of hair phenotypes in spontaneous mouse mutants or genetically engineered mice (GEM) with precisely defined lack-of-function or gain-of-function mutations has provided invaluable mechanistic insights into the – as yet often unknown or ill-understood – causes of human hair growth disorders. The range from genodermatoses (e.g. papular atrichia, monilithrex, hypotrichosis simplex) via immunological disorders (e.g. alopecia areata, autoimmune cicatrical alopecias) to hormone-dependent abnormalities (e.g. androgenetic alopecia). While caution is advised to avoid oversimplistic equations between animal models and human hair disease, mutant mice certainly offer excellent clues to specific disease mechanisms, which can be followed-up in the human system. Mouse mutants with a hair phenotype are therefore an invaluable tool for improving our often very limited understanding of human hair pathology, and are likely to generate important new insights into the molecular basis of different types of alopecia, atrichia, hypotrichosis, hair shaft disorders, hirsutism and hypertrichosis. The current mini-review is presented mainly in the form of annotated tables, and constitutes an update of earlier tabulated review that we had published more than a decade ago [3]. Numerous novel mouse mutants with a hair phenotype have been published since, justifying an extensive up-date. The present, updated tables list a wide selection of mouse mutants with hair growth abnormalities, while mutants in which the primary phenotype abnormalities lie in hair pigmentation or in the sebaceous gland were omitted. The mouse mutants with a hair phenotype presented here have been classified into four categories: mutations that affect HF (1) morphogenesis, (2) cycling, (3) structure, and (4) mutations that induce extrafollicular events, for example immune system defects, resulting in secondary hair growth abnormalities. These updated tables also should facilitate comparisons between the hair phenotype of a newly generated mouse mutant with existing ones. 2. Analysis of hair follicle morphogenesis and cycling: the importance of professionally executed, quantitative histomorphometry HF morphogenesis is focally initiated via an inductive signaling exchange between epidermal keratinocytes which eventually adopt a HF fate, and a specialized population of dermal fibroblasts, which at first form the dermal condensate and at later stages the follicular dermal papilla (DP) [1]. This bi-directional epithelialmesenchymal interaction is governed by a tightly controlled balance between numerous growth stimulators and inhibitors, which drive the developing HF through defined, genetically programmed series of morphogenetic stages that culminate in the formation of a fiber-producing mini-organ [2]. Once HF morphogenesis is completed, the HF continuously undergoes regular cycles of regeneration coupled with an extremely high proliferation and protein synthesis activity

(anagen), followed by an apoptosis-driven organ involution (catagen) and a relative resting phase (telogen) [1,2]. Similar to HF development, HF cycling is governed by signaling interactions between the dermal papilla cells and HF keratinocytes. Numerous soluble factors, transcription factors and adhesion molecules play indispensable roles in these signaling interactions. While, in contrast to human HFs, hair shaft shedding (exogen) in mice is an actively regulated process, the old hair shafts from preceding cycles are often retained by healthy murine HFs, at least during the first few cycles [4,5]. Therefore in mice even substantial abnormalities of HF cycling are not necessarily associated with substantial hair loss (alopecia), and can easily be missed, if quantitative hair cycle histomorphometry is not performed (see below). Using comprehensive guides for recognition and classification of distinct stages of murine HF morphogenesis [6] and hair cycling [7], it has become easier to compare mutant with control mice. However, four routine mistakes frequently obstruct a professional hair phenotype analysis of mutant mice: 1) Investigators tend to erroneously equate HF morphogenesis with what they consider to represent the ‘‘first hair cycle’’. These investigators ignore that HF morphogenesis in mice continues well into the first week of postnatal life and is only terminated by the induction of HF cycling when the HF first enters catagen between P17 and P19. As HFs which are still undergoing development are biologically distinct entities from mature, cycling HFs, this can lead to erroneous assumptions and illfounded hypotheses. Thus, postnatal HF morphogenesis and HF cycling must be carefully distinguished, and should be analyzed separately (for details, see Sections 5–7). 2) Hair growth phenotype analysis is often performed only on the basis of very limited qualitative comparisons between agematched mutant and wild type mice. This tends to both overinterpret and overlook phenotypic abnormalities. Therefore, a fully quantitative assessment of HF morphogenesis and cycling, which can be complemented with a ‘‘hair morphogenesis score’’ (HMS) and a ‘‘hair cycle score’’ (HCS), is mandatory for a professional hair phenotype analysis (details, Sections 5–7). 3) Murine HFs come in several important anatomical varieties with distinct structural characteristics: vibrissae HFs, and guard HFs (syn. Tylotrich HFs), auchenne, awl and zigzag pelage HFs [4]. The development of these functionally and structurally distinct HF subpopulations is induced at different time points of fetal, perinatal, and/or postnatal life, and their molecular controls can differ substantially. Thus indiscriminately lumping together these distinct HF subpopulations during hair phenotype analysis is both inaccurate and inappropriate. This obscures important molecular pathobiology clues that a separate analysis of individual HF sub-types would have revealed otherwise. 4) Distinct pelage HF subpopulations begin to develop in waves in defined skin regions, and then go on to cycle in wellsynchronized waves, which finally break-up into isolated cycling domains that subsequently become ever-more heterogeneous with progressing age of the mouse. Therefore, it is absolutely critical for professional hair phenotype analyses to not only carefully age-match mutant mice with WT controls – ideally gender-matched littermates – but also to only compare standardized identical reference areas of pelage hair. If these frequent mistakes are avoided, the hair phenotype analyses of loss-of-function and gain-of-function mice will further deepen our understanding of the functional roles of the mutated proteins in skin and hair biology, and will offer invaluable pointers to mechanisms underlying comparable human hair diseases.

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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3. Mouse models with spontaneous or randomly induced mutations Mouse models occupy a preeminent position in biomedical research. The reasons include (1) similarities between mice and humans in development, body plan, physiology and diseases; (2) the small size of mice and their large litters facilitating the maintenance of a large number of individuals; (3) over 99% of human genes have homologues in the mouse genome; (4) availability of techniques to alter gene expression efficiently and precisely. The analysis of mice carrying genetic mutations also has greatly contributed to the advance of dermatological research [4]. Initially, investigators had to rely exclusively on spontaneous mutations or mutations induced randomly by chemical or physical agents, and dozens of spontaneous mutant lines with a skin phenotype are still being used for a variety of skin research studies [4]. Often, the genetic defect underlying the spontaneous mutation was unraveled only decades after the initial description of the mouse line by gene mapping, sequencing and positional cloning techniques, or by targeted mutagenesis of the cognate gene (see below). Examples include nude mice (Foxn1 mutation), hairless mice (Hr mutation), angora mice (fibroblast growth factor 5 mutation), waved-1 and waved-2 mutant lines, recognized by their wavy hairs, (transforming growth factor-a and epidermal growth factor receptor mutation, respectively), or tabby, downless and crinkled mice (tumor necrosis factor receptor family members EdaA1, Edar and Edaradd mutations, respectively) [8–12]. Artificially induced mutations in the mouse genome allow to generate chromosomal aberrations, point mutations, deletions or insertions, depending on the method employed. Chemically induced mutations have experienced a renaissance in the form of large scale, often multi-national mutagenesis programs [13,14]. In most cases, N-ethyl-N-nitrosourea (ENU), a powerful mutagen that acts predominantly on premeiotic spermatogonia, is used. The phenotype screening of large numbers of ENU-mutated mice by specialized labs guarantees the accurate characterization of a great number of mutants. Both spontaneous and ENU-induced mutations are commonly classified as ‘‘forward genetics’’ or ‘‘phenotype-driven’’ approaches, because the mutations are induced at random, the new mutants are identified by phenotype screens, and the altered genes are only identified subsequently. 4. Transgenic mice and choice of promoters With the availability of recombinant DNA technology in the 1970s, genotype-driven approaches (also known as ‘‘reverse genetics’’) became possible. The feasibility of genome sequencing and identification of an increasing number of genes and their protein products called for their functional analysis in the organism or a in given tissue. Thus, soon after the introduction of transgenic mouse technology in the early 1980s [15], researchers increasingly concentrated on the development of methods allowing tissue-specific expression of diverse soluble factors, their receptors, transcription factors, and enzymes. The expression of keratin (K) gene pairs, which encode the major structural proteins of mammalian skin epithelium [16,17], is tightly regulated at the transcription level in keratinocytes, rendering keratins a convenient and unrivaled set of markers for the study of epithelial biology. Certain keratin promoters were also successfully exploited for directing the expression of transgenes to specific epithelial compartments, including the HF [18]. The K14 [19] and K5 [20] regulatory sequences are the most commonly employed promoters to drive transgene expression in the basal layer of the epidermis and the outer root sheath of the HF, while the K1 [21] and K10 [22] promoters target terminally differentiated epidermal keratinocytes. More recently, the K15 promoter was

3

shown to be a particularly useful tool for targeting HF epithelial stem cells [23,24]. Additional promoters are employed in hair research to achieve cell type-specific expression of transgenes include the regulatory sequences of involucrin [25,26], versican [27], and msx2 [28] genes. Since most of the commonly employed promoters are already active during embryonic development and may therefore interfere with experiments focusing on hair cycling and homeostasis in adult epidermis, a major advance in transgenic technology was the introduction of inducible expression systems. The most popular approach is the Tet-Off or Tet-On expression system, in which the expression of the transgene depends on the activity of an inducible transcriptional activator, the tetracycline transactivator (tTA or rtTA) [29]. In both systems, the activity of tTA/rtTA and, thus, expression of the transgene can be quantitatively and reversibly regulated by exposing the animals to varying concentrations of tetracycline or, most commonly, its derivate doxycycline in drinking water or food pellets [30,31]. Hair-specific expression of Cre under the control of tTA/rtTA is achieved most commonly by employing the K5 [32] and K14 [33–35] regulatory regions [reviewed in 18]. 5. Targeted mutagenesis In contrast to the random integration of constructs in transgenic technology, gene targeting by homologous recombination permits the modification of specific endogenous sequences [36]. The gene of interest can be completely inactivated, resulting in the constitutive loss of the equivalent protein (‘‘knock-out’’). Another possibility is the replacement of the endogenous gene with a similar sequence carrying a subtle mutation, or with an exogenous coding sequence to take advantage of the regulatory promoter elements of the locus (‘‘knock-in’’). The latter method is also frequently used to introduce reporter genes, such as different fluorescent proteins or b-galactosidase, into a particular gene locus for detecting expression patterns and for lineage tracing studies [18]. A more accurate analysis of gene function and regulation is achieved by conditional mutagenesis, a technique allowing tissuespecific and time-controlled modification of gene product activity. In the P1 bacteriophage-derived Cre-loxP system, the enzyme Cre (creates recombination) recombinase recognizes a 34 bp-long sequence called loxP (locus of crossover in P1). Cre excises DNA segments flanked by two loxP sites in the same orientation, leaving a single loxP site behind. This property is exploited in a binary mutant approach, where mice expressing Cre are crossed to mice carrying gene segments flanked by two loxP sites (‘‘floxed’’). The K5 [37,38] and K14 [39] promoters are the most commonly employed regulatory regions to direct expression of Cre in hair research [reviewed in 18]. In addition to the transgenic approach, some Cre expressing lines such as K14-Cre [40] and Krox20-Cre [41] have also been generated with a knock-in approach. Apart from specifically knocking out a gene in a particular tissue by the Cre-loxP system, temporal control can be achieved by the expression of Cre recombinase fused to a mutated ligand-binding domain of the estrogen receptor that binds tamoxifen, but not estrogen. In this case, Cre activity is only present after administration of the estrogen agonist tamoxifen [42]. Again, hair-specific expression of Cre is achieved most commonly by either employing the K5 [43] or K14 [44] regulatory regions [reviewed in 18]. Initially, gene-targeted mouse models were laborious and timeconsuming products. However, the availability of the human and mouse genome sequences and many technical advances contributed to the simplification and automatization of the procedure. It is, thus, noteworthy to mention the bacterial artificial chromosome (BAC)-based high-throughput VelociGene system, which allows precise genetic alteration independently of the size of the desired

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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4

Table 1 Mouse mutants with reported hair follicle morphogenesis abnormalities. Abbreviations: Ch, chromosome; IRS, inner rooth sheath; ORS, outer rooth sheath; Tm, targeted mutation; Tg, transgenic; S, spontaneous; Rad, radiation induced; UN, unknown. Mutant name Soluble factors and receptors Activin A receptor, type 1

Symbol

Ch

Acvr1

Type

Abnormalities

Reference

Tg

S1

EdaTa6J, EdaTa, EdaTac

X

S

EdaTa6J Tnfrsf19 (Troy)

X 14

S Tm

Edardl3J

10

S

At P1, retardation of HF morphogenesis. Identical phenotype to TGFa KO mice (see below): Wavy hair and curly vibrissae due to HF orientation and alignment problems. At P1, retardation of HF morphogenesis. Lack of IRS and hair shaft formation: BMP signaling required for hair shaft and IRS differentiation. Accelerated HF morphogenesis. Impairment of IRS differentiation. No or abnormal hair shafts. Most of the hairs fail to pierce the epidermal surface. At P8, wavy hairs, lack of IRS and hair shafts. No IRS or hair shaft differentiation. Complete absence of HF development Hair growth from corneal epithelium. Continuous placode formation between E14 and birth. Longer and wavy hairs with abnormal ultrastructure. No zigazag hairs, only guard and awl hairs. Bald patch behind the ears and no hair on the tail. Mice only develop awl hairs. Lack of guard hair development. Lack of formation of zigzag hair ultrastructure. Zigazgs are transformed in awl hairs. Guard hair development can be restored by transgenic overexpression of Eda-A1 (K14Eda-A1), but not zigzag hair formation. Guard HF placode development initiated, but no down-growth. Double mutant with tabby phenotype, but also focal alopecia on head and retarded secondary HF development. Identical to tabby mice.

10

S

Identical to tabby mice.

S19

10 10

S Tg Tg

Identical to tabby mice. Identical to tabby mice. 40% increase in HF placode density. Retarded HF development at P4 Short and waved hairs and curly whiskers. Thinning or loss of the inner and outer root sheath in 3 to 4 weeks old mouse. Degeneration and destruction of HFs. Delay of HF development. At P5, disoriented and irregularly placed HFs. Premature separation of hair shaft from IRS. Premature keratinization of IRS. At P7, no hair outgrowth. Short curly vibrissae. Disoriented HFs. Few hairs grow through the epidermis.

S20 S21 S22

Amphiregulin/Epidermal growth factor/ Transforming growth factor a triple knockouts

Aregtm1Dle Egftm1Dle Tgfatm1Unc

Betacellulin

Tg(CBA-Btc)2Ewo

Bone morphogenetic protein receptor, type 1A, epidermal Tm

Bmpr1afl/fl K14-Cre

14

Tm

Bone morphogenetic protein receptor, type 1A, skin Tm

Bmpr1aflox/ Emx1Cre/+

14

Tm

Bone morphogenetic protein receptor, type 1A, epidermal Tm Bone morphogenetic protein receptor, type 1A, epidermal Tm Dickkopf 1

Bmpr1atm2Bhr Tg(KRT14-cre)40Smr Bmpr1atm2Bhr KRT14-cre K14-Dkk1 K5rtTA;tetO-Cre;Dkk1 Dkk2tm1Lmgd

14

Tm

14

Tm

Dickkopf 2 Ectodysplasin-A1, epidermal over-expression

Ectodysplasin-A1

Tabby 6 Jackson, tabby and tabby c

Ectodysplasin-A receptor Ectodysplasin-A receptor Ectodysplasin-A receptor Ectodysplasin-A receptor, epidermal over-expression Epidermal growth factor Epidermal growth factor receptor ERBB1, dominant negative

Downless 3 Jackson Sleek Downless

Dlslk

Edar , Transposon induced. Edardl EdarTg(OVE1B)Ove K14:LMP1-Edar

Tm Tm Tm

Tg

Tg 3

Tm Tg

mEda-A1, K14-Eda-A1, Ivl-Eda-A1

Ectodysplasin-A1 and Tumor necrosis facor receptor superfamily, member 19 Ectodysplasin-A receptor

5 3 6

CMV-Egf Tg(EGFR)0Jlj

Tg Tg

Epidermal growth factor receptor

Egfrtm1Mag

11

Tm

Epidermal growth factor receptor

Egfrtm1Rdk

11

Tm

S2

S3 S4

S5

S6 S7 S8–9 S10 S11–13

S14–17

S18

S23 S24

S25

S26

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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Table 1 (Continued ) Mutant name

Symbol tm1Wag

Ch

Type

Abnormalities

Reference

11

Tm

At birth, less differentiated HFs. At birth, vibrissae are absent or rudimentary stubs. Delay of HF development. Short and sparse hairs. At 3 months, degenerated HFs. Progressive hair loss. A wavy coat in 3-week-old animals that becomes less apparent with age Wavy hair and curly vibrissae. Wavy, disoriented hairs. Curly vibressae. Wavy hair and curly vibrissae. Ptpn11 heterozygous background results in no or few poorly developed and disordered HFs and little hair outgrowth. Majority of the HFs replaced by bizzare hyperproliferative intradermal squamous invaginations. Patchy hair growth, follicular hyperplasia Alopecia, follicular hyperplasia

S27

Epidermal growth factor receptor

Egfr

Epidermal growth factor receptor, ‘‘humanized’’ mice; hypomorphic receptor

Egfrtm2(EGFR)Wag

11

Tm

Epidermal growth factor receptor

Dark skin 5

EgfrDsk5

11

ENU

Epidermal growth factor receptor Epidermal growth factor receptor

Waved 5 Velvet

Egfrwa5 EgfrVel

11 11

ENU ENU

Epidermal growth factor receptor Epidermal growth factor receptor, ‘‘humanized’’ mice; hypomorphic receptor. Protein tyrosine phosphatase, non-receptor type 11

Waved 2 Waved 2

Egfrwa2 Egfrwa2 Ptpn11tm1Pau

11 11 5

S S Tm

Avian erythroblastosis oncogene B2 (neu; activated ERBB2)

Tg(erbb2*)1Jek

Tg

Avian erythroblastosis oncogene B2 (neu; activated ERBB2) Avian erythroblastosis oncogene B2 (neu; activated ERBB2) Fibroblast growth factor 7 (Keratinocyte growth facor) Fibroblast gowth factor 7 (keratinocyte growth factor)

Tg(K5-erbb2*)

Tg

Tg(K5-erbb2*)

Tg

FGF7tm1Efu

2

Tm Tg

Tg(FGF7)2Efu

Fibroblast gowth factor 10

Fgf10tm1Ska

13

Tm

Fibroblast growth factor receptor 2 Fibroblast growth factor receptor 2

Fgfr2tm2.1Dsn Fgfr2tm3Dsn

7 7

Tm Tm

Fibroblast growth factor receptor 2

Fgfr2tm1Cxd

7

Tm

Fibroblast growth factor receptor 2 (dominant negative) Follistatin

Tg(FGFR2)1Saw

Follistatin

Tg(Fst)4Zuk

Frizzled 6 Human glucocorticoid receptor DNA binding factor 1 Hepatocyte growth factor Insulin-like growth factor Insulin-like growth factor Insulin-like growth factor

Fzd6tm1Nat Grlf1

Insulin-like growth factor I receptor

Igf1rtm1Arge

Insulin-like growth factor binding protein 3

Igfbp3

Inhibin bA (Activin bA)

Inhbatm1Zuk

13

Tm

Inhibin bA (Activin bA)

Inhba

13

Tm

Mitten

Inhba Lrp4mitt

2

Tg ENU

Mitaine

Lrp4mta

2

ENU

Inhibin bA (Activin bA) Low density lipoprotein receptor-related protein 4 Low density lipoprotein receptor-related protein 4

tm1Zuk

Fst

Tg UN

Tm

Tg 15

Tg(Hgf)1Paus Tg(IGF1)1Hys Tg(IGF1)Jdg IGF1

Tm Tg Tg Tg Tg Tg

7

Tm

Tg

Perturbation in the direction of the hairs. Marked suppression of HF morphogenesis.Sparse or no whiskers. Decreased number of hair follicles. Elongation of hair follicles rarely seen. Thin hairs. Disorganized HFs. At E13.5 and E14.5, no placode formation. Reduced HFs. Retarded HF development. No placode formation at E14.5. Decreased hair density after skin transplantation to wildtype recipients. 60–80% reduction in the number of HFs. Thin and inappropariately oriented vibrissae. Retardation of HF development. Irregular fur. No obvious cause found histologically. HFs in divergent orientation. Expression in embryos results in reduced HFs. Accelerated HF development. Accelerated vibrissae growth Earlier HF development. Earlier HF development. 10% longer awl hairs and 20% longer guard hairs compared to the wild-type. Marked decrease in the absolute number of HFs. Smaller HFs. Slight delay in HF development. Reduced size of HFs. Less dense and rough appearance of hairs. Lack of vibrissae (pelage HFs apparently normal). Inhibin ba is replaced with Inhibinbb. Rough appearance of hairs. Slower hair growth. Retardation of HF development. Not specified abnormal HFs and vibrissae. Not specified abnormal HFs and vibrissae.

S28

S29

S30 S31 S32–33 S34

S35–36

S37 S38 S39 S40

S41

S42 S43

S44

S45 S46–47

S48 S49 S50 S51 S52 S53 S54

S55

S56

S57 S58

S47 S59

S59

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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6 Table 1 (Continued )

Mutant name Low density lipoprotein receptor-related protein 6 Nerve growth factor Nerve growth factor, epidermal over-expression Nerve growth factor, transgenic expression of antibodies against NGF under the CMV promoter Nerve growth factor receptor (p75) (low affinity neurotrophin receptor)

Crooked

Symbol

Ch

Type

Abnormalities

Reference

Cd

Lrp6

6

S

Short and bristle-like hairs.

S60

NGFtm1Gne K14-NGF

3

Tm Tg

Retarded HF development. Acceleration of HF morphogenesis. Retardation of HF development.

S61 S62

Acceleration of HF morphogenesis. Prominant upregulation of Fgfr2 in both follicular dermal papilla and epithelium. Reduced number of HFs; no secondary HF development. Increased awl-like hairs due to conversion of zigzag and auchene into awl hairs. Enlarged hair bulbs of anagen HFs. Increased hair density. Increased numbers of auchene and awl hairs. At P7, hairless. Hyperplastic and disoriented HFs. Only zigzag hairs were present. At P52, HFs were filled with sebocytes. Retarded HF development.

S64

Tg(CMV-VH-aD11), Tg(CMV-VK-aD11)

Tg

Ngfrtm1Jae

11

Tm

Noggin

Nogtm1Amc

11

Tm

Noggin, epidermal over-expression

Nog, K5-Noggin

Tg

Noggin, epidermal over-expression

Nog, K14-Noggin

Tg

Neuregulin 3

Nrg3

Tg

Neurotrophic tyrosine kinase receptor, type 3 (TrkC) Neurotrophin 3

Ntrk3tm1Bbd

Neurotrophin 3

tm1Jae

Ntf3 Ntf3tm2Jae Tg(Ntf3)1Kma

7

Tm

6

Tm Tg

Nuclear receptor subfamily 3, group C, member 1

Nr3c1

Platelet derived growth factor a

Pdgfatm1Cbet

Peroxisome proliferator activatorreceptor a Peroxisome proliferator activator receptor d Parathyroid hormone-like peptide

Tg(tetO-PPARA)1Gonz

Parathyroid hormone-like peptide Homeobox, msh-like 2 (Msx-2) Sonic hedgehog homolog, transgenic over-expression under the human keratin 1 promoter

Tg(PTHLH)7Wmp Msx2tm1Rilm HK1-Shh

13

Sonic hedgehog homolog

Shhtm1Amc

5

Tm

Sonic hedgehog homolog Smoothened homolog (Drosophila)

Shhtm1Chg Smo

5

Tm Tg

Smoothened homolog (Drosophila): epidermal expression of the oncogene M2SMO together with transgenic epidermal Dickkopf homolog 1 expression

K5-M2SMO K5-Dkk1

tm1Wwah

Ppard

Tg

5

Tm Tg

17

Tg(PTHLH)7Wmp

Tm Tg

Tg Tm Tg

Tg

Retarded HF development in heterozygotes. Accelerated HF development and increased number of HFs. Reduction in the number of HFs (50%). Atrophic HFs. HFs are replaced by hypertrophic sebaceous glands. Misshapen HFs, smaller dermal papillae, thinner hairs. Reduction in the number of HFs. Thin hairs. At P4, retarded HF development. Ventral hairlessness (almost complete absence of HFs). Short and thin hairs on the dorsum. A delay of hair follicle morphogenesis. Recovery of HF induction in ventral skin. Suppression in HF development between E14 and E19: Total lack of guard, awl, and auchene hairs. Only develop (90%) zigzag hairs. Alopecia on the head. Total arrest of HF development at peg stage. Retarded HF development. Rudimentary DP. Absence of IRS development. No HF formation in skin grafts. Identical to Shhtm1Amc. Overexpression of human SMO with a mutation resulted in ectopic epithelial buds and follicular hamartoma formation. Ectopic epithelial HF bud formation caused by constitutive SHH activity in K5M2SMO mice is blocked by epidermal WNT activity inhibition (K5-Dkk1).

S63

S65 S66

S67

S68

S69 S70 S70 S71

S72 S73 S74 S75

S76 S77

S78

S79 S80

S80

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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7

Table 1 (Continued ) Mutant name

Symbol tm1Amc

Ch

Type

Abnormalities

Reference

Tm

Mice have decreased epithelial and increased mesenchymal SHH signaling. At P1, abnormal epithelial invagination. At 2–3 months of age, huge HFs. De novo HFs from ORS and interfollicular epithelium. Abnormal hair shaft and IRS formation. Cyst formation. Eventual depletion of HF stem cell niche. Reduced HFs at E17.5 and P0. Retarded HF morphogenesis at P0 and P3. Pronounced waviness of the vibrissae and fur. Abnormal curvature and disorientation of the HFs. Disheveled hairs pointing in different directions in different angles. Additional bends in hair shafts. Wavy hair and curly vibrissae due to disorganization of HFs. Flattened and distorted HFs at the dermal-subdermal border. Reduction in the number of HFs. 50% reduction in the number of HFs on day E18.5. Delay in HF morphogenesis. Retarded hair growth. Shorter HFs and distorted at the base of the muscle layer.

S81

Smoothened homolog (Drosophila)

Smo Tg(KRT-14-cre)1Amc

6

Smoothened homolog (Drosophila)

Smotm2Amc Tg(Prrx1-cre)1Cjt/J

6

Transforming growth factor a

Tgfatm1Ard

6

Tm

Transforming growth factor a

Tgfatm1Unc

6

Tm

Tgfawa1

6

S

Transforming growth factor a

Tg(Tgfa)1Efu

6

Tg

Transforming growth factor b1

Tg(Tgfb1)1Der

7

Tg

Transforming growth factor b2

Tgfb2tm1Doe

1

Tm

Tumor necrosis factor, epidermal over-expression

Tnf, K14-TNF

Transforming growth factor a

Transcription factors Activating transcription factor 3

Waved 1

Tg

Tg(KRT5-ATF3)1Mcld

1

Tg

Activating transcription factor 4

Atf4tm1Tow

15

Tm

Catenin (Cadherin associated protein) b1. Overexpression of stabilized b-catenin.

Ctnnb1(Ex3)fl

9

Tm

Catenin (Cadherin associated protein) b1. Overexpression of stabilized b-catenin.

Ctnnb1(Ex3)fl

9

Tm

Catenin (Cadherin associated protein) b1. Epidermal Tm

Ctnnb1tm4Wbm, Krt14tm1(cre)Wbm

9

Tm

Catenin (Cadherin associated protein) b1. Epidermal Tm Catenin (Cadherin associated protein) b1, ventral dermis Tm Catenin (Cadherin associated protein) b1, dermal Tm Catenin (Cadherin associated protein) b1

Ctnnb1fl/fl, KRT14-Cre line 43 Ctnnb1

9

Tm

9

Tm

Ctnnb1D/fl, En1Cre

9

Tm

(Ex3)fl

9

Tm

Ctnnb1 HoxB6CreER

At P17, multiple layers of hyperplastic ORS cells. Large aberrantly shaped HFs. Delay of hair growth. By one week of age, homozygous mice have only fine sparse haris. Many have ruffled hairs. Placode-like structures already at E12.5. At E14, high placode density. At E17, the downgrowth of HF placode ceases. Irregulary-spaced placodes. Impaired hair shaft formation. Premature placode development already at E12.5. Entire epidermis adopts HF fate, even on foot pads. At E14.5, failure of HF invagination into the dermis. Ectopic HFs also in adults when over-expressed in adult ectoderm. Lack of hair shaft formation. At P8, patches of hairless skin. Reduced zigzags. At P20, retracting epithelial hair shafts become separated from the dermal papillae. Hair loss progressed after P16. Total hair loss at P30. Late induction of K14-Cre. Complete absence of HF development. At E14.5, absence of ventral HFs. Complete absence of HF development. Forced expression of b-catenin in dermal fibroblasts leads to the increase in HF placode size and number.

S82

S83

S84

S85–86 S87 S88 S89

S90

S91

S92

S93

S94

S95

S9 S96 S97 S97

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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8 Table 1 (Continued )

Mutant name

Symbol

Ch

Type

Abnormalities

Reference

Tg

High amounts of abnormal ectopic hair follicles observed from P18 onwards. Hair-germlike structures progress to epithelioid cysts, tumors resembling trichofolliculomas or pilomatricomas. Curly vibrissae and wavy hairs. HFs are rooted more deeply and are mildly disorganized. HFs appeared greater in number and somewhat disorganized. At 1 week after birth, homozygotes started to lose hairs. Twisted, bifurcated, circle, and corkscrew hairs with nodules or longitudinal grooving. Disoriented HFs. At P9 no apparent medulla.

S98

Catenin (Cadherin associated protein) b1. Epidermal N-terminally truncated b catenin expression

Tg(CTNNB1)1Efu: K14-DN87bcat

Cut-like homeobox 1

Cux1tm2Ejn

5

Tm

Cut-like homeobox 1

Cux1tm1Rhsc

5

Tm

Cut-like homeobox 1

Cux1tm1Mbu

5

Tm

Distal-less homeobox 3 Epidermal Tm

Dlx3tm2Mso Tg(KRT14-cre)Smr Tg(KRT5-E2F1)1Dgj

11

Tm

2

Tg

E26 avian leukemia oncogene 2,30 domain

Ets2tm1Rgo

16

Tm

Forkhead box E1 (thyroid transcription factor 2)

Foxe1tm1Rdl

4

Tm

GATA binding protein 3 Epidermal Tm

Gata3tm3Gsv Tg(KRT14-cre)8Brn Gli2tm1Alj, K5-Gli2, K5-DNGli2

2

Tm

1

Tm and Tg

Interferon regulatory factor 6

Irf6tm1Mjd

1

Tm

Lymphoid enhancer binding factor-1 (Lef-1)

Lef1tm1Rug

3

Tm

Lymphoid enhancer binding factor-1 LIM homeobox protein 2 Homeobox, msh-like 2 (Msx-2)

Tg(LEF1)1Efu

3

Tg

Lhx2tm1Dra Msx2tm1Rilm

2 13

Tm Tm

Homeobox, msh-like 2 (Msx-2)

Tg(Msx2)1Rem

Tg

Nuclear factor of kappa light chain gene enhancer in B-cells (NF-kB)

Ctnnb1tm1(Nfkbia)Rsu, IkBaDN

Tm

E2F transcription factor 1. Epidermal over-expression of E2F1

GLI-Kruppel family number 2 (Gli2): Gli2 Tm, epidermal Gli2 over-expression and epidermal hyper-active Gli2 over-expression

A reduced number of hair follicles. Many TUNEL positive cells in the developing hair follicles. Wavy hair, curly vibrissae, abnormal HF shape and arrangement. Sparse, kinky hairs, misaligned, variably angled, small HFs in skin grafts. Reduced awls and auchenes. At P10, retarded HF development. At E18.5, HFs are arrested at the early hair peg stage. Fewer and less developed vibrissae follicles. Essentialy hairless skin grafts. Transgene of Gli2 (K5-Gli2) partially rescues HF development, and skin grafts produce HFs. Expression of DNGli2 (hyperactive Gli2; K5DNGli2) recues the delay of HF development in Shh knock-out mice. At E16, retardation of HF development. Lack of whiskers and body hairs. An arrest in development at a stage corresponding to E17. No secondary HF development. Total lack of whisker development. Irregularly spread and oriented HFs and curly vibrissae. At E16, 40% fewer HFs. Msx2 is not required for HF initiation, but for maintenance: Msx2/ mice loose all hair by P14. Misaligned HFs with a shrunken matrix region. Hair shafts with irregular angles. Thinner outer root sheath. Expression of the NFkB superrepressor IkBaDN (DN) results in an identical HF phenotype as in tabby, downless and crinkled mice: Bald patch behind the ears, no hair on tail, only one coat hair type (awl hairs), no development of guard hairs. 50% less HF than in wild-type mice. Guard HF development initiates (up to stage 0/1), but no placode down-growth.

S99

S100

S101

S102 S103

S104

S105

S106 S107

S108 S109

S110 S111 S112

S113

S114

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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9

Table 1 (Continued ) Mutant name

Symbol tm1Grd

Ch

Type

Abnormalities

Reference

At E16, no placode formation similar to IkBaDN, downless and tabby mice: No guard hairs. At E18, retarded HF development (secondary HF development), 70% reduced HFs. Sparse hairs on the skin grafts. Delay of HF development at E18.5 and E19.0. At P1, delay in HF morphogenesis. Lack of hair shaft formation. Sparse and curly vibrissae. Disoriented and disorganized HFs. Delay of HF morphogenesis by activation of transgene expression between E10.5– 14.5. More severe delay of HF morphogenesis than Smad7 single transgenic mice due to suppression of BMP and WNT signaling. Degenerated HFs. Lack of surface hair and cyst formation. Disheveled hairs. Size and length reduction of hair shafts. Deformation of HFs. Bald spots. Increased zigzags, reduced awls. Increased zigzags, reduced awls. Atrophic, small hairs do not develop any HF stem cells. Absence of bulge Sparse hairs.

S115

Hypoplasia of selected pelage follicles. In heterozygous ragged: The coat contains guard hairs and awls but no auchenes or zigzags. Homozygous mice lack pelage hair and vibrissae entirely. Heterozygotes have very sparse hairs consisting mostly of Reduced zigzag hairs. Complete absence of HF development. At P1, complete lack of HFs. Not analyzed at earlier time points. Presumably identical to Trp63tm1Brd. Forced expression of DNp63 results in replacement of hair shafts by thick keratinized tissues. Conditional double deficient mice lacked vibrissae. Reduction in the number of HFs by 50%. Absence of vibrissae. Sparse hairs. Reduced and distorted HFs.

S123–124

NF-kB RelA, NF-kB c-Rel, Tumor necrosis factor

, Triple Tm: Rel Relatm1Bal, Tnftm1Ljo

11, 19, 17

Tm

Runt related transcription factor 2

Runx2tm1Mjo

17

Tm

SMAD7

K5.Smad7

18

Tg

SMAD7

K5.Smad7

18

Tg

SMAD7, epidermal over-expression. SMAD specific E3 ubiquitin protein ligase 2, epidermal over-expression. Double Tg

K5.Smad7 K5.Smurf2

18 11

Tg Tg

SMAD7, epidermal over-expression

K5.Smad7

18

Tg

Sox2lcc

3

Rad

Sox2

3

Tg

Sox9flox/flox hWT1-Cre (Y10:Cre)

11

Tm Tg

Sox18Gsfdcc1

2

ENU

2

S

SRY-box containing gene 2 SRY-box containing gene 2

Light coat and cycling Yellow submarine

SRY-box containing gene 9 (Sox9). Skin KO SRY-box containing gene 18

ysb

SRY-box containing gene 18

Gsf dark coat color 1 Ragged

Sox18

SRY-box containing gene 18

Opossum

Sox18Raop

2

S

SRY-box containing gene 18

Sox18tm1Koop

2

Tm

Transformation related protein 63

Trp63tm1Brd

16

Tm

16

Tm

Ra

tm1Fmc

Transformation related protein 63

Trp63

Transformation related protein 63

K5-tTA/pTRE-DNp63a

Transcription factor AP-2,a Transcription factor AP-2,g Trichorhinophalageal syndrome type I (human) Twist 2 Enzymes Acid phosphatase 2, lysosomal

Naked and ataxia

A disintegrin and metalloproteinase

ATPase, Cu2+ transporting a polypeptide ATPase, Cu2+ transporting a polypeptide

Mottled Brindled

Tg

K14-Cre Tfap2atm3Will Tfap2ctm1Will Trps1tm1.1Shiv

13 2 15

Tm Tm Tm

Twist2tm1Eno

1

Tm

Acp2nax

2

S

Adam17tm1Imx

12

Tm

Atp7aMo

X

S

X

S

Mobr

Atp7a

Delayed hair appearance. Lumbar skin HFs contained extremely thin and short hair shafts. Stunted and curly vibrissae. Irregularly positioned and oriented hair follicles. Curly vibrissae evident within the first day of life. Curly vibrissae in heterozygous females. Strongly curled vibrissae and wavy coat in heterozygous males.

S116 S117

S118

S119

S119

S120 S120 S121–122

S29

S125 S126 S127 S128 S129

S130 S131 S132

S133

S134

S135 S136–137

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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10 Table 1 (Continued )

Mutant name 2+

Symbol

Ch

Type

Abnormalities

MobrJ

Reference

ATPase, Cu transporting a polypeptide ATPase, Cu2+ transporting a polypeptide

Brindled Jackson Dappled

X

S

Curly vibrissae.

Modp

Atp7a

X

Rad

S138

ATPase, Cu2+ transporting a polypeptide ATPase, Cu2+ transporting a polypeptide

Macular

Atp7aMoml

X

S

Heterozygous females are similar in color and curliness of vibrissae to Mo/+ females. Curly vibrissae.

Mosaic

Atp7aMoms

X

S

S140

ATPase, Cu2+ transporting a polypeptide ATPase, Cu2+ transporting a polypeptide UDP-Gal:bGlcNAc b1,4-galactosyltransferase, polypeptide 1 Conserved helix-loop-helix ubiquitous kinase

Tortoiseshell

Atp7aMoto

X

S

Heterozygous females have normal-colored and mutant hairs arranged in an irregular pattern of transverse bars. Slight wavy vibrissae.

Viable brindled

Atp7aMovbr

X

S

Curled vibrissae.

S142

B4galt1tm1Shur

4

Tm

Sparse hairs. Reduction in the density of hair follicles.

S143

Chuktm1Aki

19

Tm

S144–145

Ctsbtm1Jde Ctsltm1Cptr Ctslnkt

14 13 13

Tm Tm Rad

Absence of vibrissae.Reduction in the number of the HFs. Failure of HFs to invaginate deeply into the dermis. At P7, delay of hair appearance.

S147

Cathepsin L

Ctsltm1Cptr

13

Tm

Cathepsin L Cathepsin L Cathepsin L

Ctsltm1Cptr Ctsl Ctsltm1Alpk

13 13 13

Tm Tg Tm

Ctslfs

13

S

Dicer1, epidermal Tm

Dicer1tm1Smr, Tg(KRT14-cre)1Efu

12

Tm

Dicer1, epidermal Tm

Dicer1tm1Tara Tg(KRT14-cre)1Efu

12

Tm

Ggta1

2

Tg

Delay of hair appearance. Complete baldness around the eyes and the head. Hair shafts are defective with dilatation of hair canals. Delayed HF morphogenesis. Defect in inner root sheath differentiation and desquamation. Dilatation of hair follicle canals. Normalization of hair morphology. Abnormal HF orientation, hair shaft fragmentation, utricles. Progressive hair loss begininng at 3 months. Short or missing vibrissae at 2 days. Shorter hairs. At P7, delay of HF development and misangled and wavy HFs. HFs fail to extend into the dermis. Much smaller hair bulbs. Keratin 15 positive cells are absent. No stem cell markers. Hair germs appear to evaginate from the epidermis. Cyst-like structures in the epidermis. Abnormal hair growth.

Double Tm: Hdac1tm1Eno Hdac2tm1Eno

4 10

Tm Tm

Integrin linked kinase

Ilktm1Ref

7

Tm

Integrin linked kinase

Ilk

7

Tm

Map2k1tm1Chrn Tg(KRT14-cre)1Efu Mapk8tm1Flv Mapk9tm1Flv

9 14 11

Tm Tg Tm Tm

Map3k7tm1Aki K5-cre

4

Tm

Cathepsin B Cathepsin L Cathepsin L

Cathepsin L

Glycoprotein galactosyltransferase a1,3 Histone deacetylase 1 Histone deacetylase 2

Mitogen activated protein kinase kinase 1. Epidermal Tm Mitogen activated protein kinase 8 Mitogen activated protein kinase 9. Double Tm Mitogen-activated protein kinase kinase kinase 7

Nackt

Furless

Atp7a

Double Tm: Total absence of HF placode formation and morphogenesis simlar to p63 KO. Distorted HFs. Impaired downward migration of progenitor cells. At 1–2 weeks, scattered hairs with partial alopecia. At 4 weeks, progressive hair loss. At P4, 55% decrease in the number of HFs. Retardation of HF morphogenesis Reduced proliferation in HFs. 37% fewer HFs. At E18.5, disorganized and immature HF development. At birth, fewer HFs. Reduced HFs at E15.5. Retarded HF morphogenesis.

S139

S141

S146

S148

S149 S150

S151 S152

S153

S154

S155

S156

S157

S158 S159

S160

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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11

Table 1 (Continued ) Mutant name

Symbol

Ch

Type

Abnormalities

Reference

Phospholipase A2, group IIA (platelets, synovial fluid)

Tg(PLA2G2A)703Dsg

4

Tg

S161

Phospholipase A2, group IIA (platelets, synovial fluid)

PLA2G2A

4

Tg

Phospholipase C, d1

Plcd1tm1Tta

9

Tm

Protease, serine 8 (prostasin)

Prss8tm1.1Hum Tg(KRT14-cre)1Ipc Psen1tm2Shn Psen2tm1Haa Tg(Msx2-cre)5Rem

7

Tm

12 1

Tm Tm Tg

Ptentm1Mak K5-cre

19

Tm

At P7–10, scruffy and sparse hairs. At P16 severe alopecia. At 3 weeks, reinitiation of hair growth. Progressive hair loss afterwards. Larger HF with some follicular keratosis In homozygotes, delay of pelage hair appearance. Lack of normal IRS or ORS. Cyclic hair growth and hair loss. At P8, hairs fail to penetrated the epidermis. Hair canals are occluded with keratinocytes. At P15, HF morphology is severely affected, forming HF-derived cysts. Reduced HFs. Retardation of HF development. Short HFs. At P4, loosely packed cells with enlarged cytoplasm in HFs. At P12 and P15, degenerating HFs lose contact with dermal papilla. By P22, cysts replace HFs. Patchy hair loss. Ruffled and shaggy hairs. High density of HFs. At P9, retardation of HF development. Misaligned HFs perpendicular to the skin surface. Reduced HFs. Sparse hairs. At 1 week, delayed HF development, pyknotic nuclei containing cells lining the HFs. Lower HF density, small dermal papilla, thin IRS and ORS. Progressive hair loss At E18.5, poorly developed vibrissae. Homozygous skin grafts are devoid of hairs. Lack of penetration of hair shafts. Curly and thin hairs. Small hair bulbs. Curly vibrissae. Sparse and frizzy hairs. Disorganized hair medulla. At P3, small hair bulbs, narrow, immature hair shaft, lack of uniform orientation. At P5, thick ORS and thin IRS. At P4, small hair bulbs. At P10 sparse hairs. Wavy hairs and curly vibrissae. Disorganized HFs lacking uniform orientation. Thin IRS and hair shafts. At P6, fewer hair bulb cells. Small and round dermal papillae. Short sparse and curly hairs. Cuticles poorly adherent to the hair shafts. Ectodermal deletion of Tpp1 resulted in the absence of mature HFs at P4.

Presenilin1 Presenilin2

Phosphatase and tensin homolog, epidermal Tm Prostaglandin-endoperoxide synthase 2. Epidermal over-expression

Prostaglandin-endoperoxide synthase 2. Epidermal over-expression RecQ protein-like 4

Tg

Tg(K5-Ptgs2)19Kmd

Tg

Recql4tm1Abe

15

Tm

Ripk4tm1Pmh

16

Tm

Fuzzy

Sgk3fz

1

S

Frowzy

Sgk3fzfy

Receptor-interacting serine-threonine kinase 4 Serum/glucocorticoid regulated kinase 3 Serum/glucocorticoid regulated kinase 3 Serum/glucocorticoid regulated kinase 3

Tg(K5-Ptgs2)19Kmd

1

S

ypc

Sgk3

1

S

Serum/glucocorticoid regulated kinase 3

Sgk3tm1Dpea

1

Tm

Serum/glucocorticoid regulated kinase 3

Sgk3tm1Efu

1

Tm

Tripeptidyl peptidase I

Tpp1

7

Tm

Adhesion molecules and their associated proteins Cadherin 1

Ypc

Cdh1

Integrin a5

Ctnna1tm1Efu, Tg K14-Cre Tg(ITGA5)0794Fmw

Integrin b1

Tg(ITGB1)0840Fmw

Catenin alpha 1, epidermal Tm

Tg 18

Tm Tg

Tg

Delay of hair follicle morphogenesis. No vibrissae. Diminished signs of hair follicle morphogenesis. Few, short, curly vibrissae. Disorganized and abnormally oriented HFs. Few, short, curly vibrissae. Disorganized and abnormally oriented HFs.

S162

S163

S164 S165

S166 S167

S168

S169

S170

S171 S172 S173

S174

S175

S176

S177 S178 S179

S179

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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12 Table 1 (Continued )

Mutant name

Symbol tm1Ref

Ch

Type

Abnormalities

Reference

Reduced number of hairs at P9. Only a few hairs are left after four weeks. At 9 days, many hair follicles show shortened hair bulb, folding of the layers of the inner root sheath cells, an increased number of outer sheath cells, and amorphous, mislocated hairs. Hair follicles do not grow into the dermis. Loss of basement membrane organization. Expression of N-terminally truncated plakoglobin protected against degradation. Hyperplasia of the HFs and dermal cysts. Novel HF buds from the ORS and from the epidermis Partial alopecia. No new hair germs or hair follicle tumors.

S180

Integrin b1, epidermal Tm

Itgb1 , Tg K5-Cre

8

Tm

Integrin b1, conditional epidermal Tm

Itgb1tm1Efu Tg K14-Cre

8

Tm

Junction plakoglobin

Jup

Tg

Jup Ctnnb1tm4Wbm Krt14tm1(cre)Wbm

Tg Tm

Junction plakoglobin Catenin (Cadherin associated protein) b1 Others Thymoma viral proto-oncogene 1

Akt1tm1Thir

12

Tm

tm1Nhy

Thymoma viral proto-oncogene 1, Thymoma viral proto-oncogene 2. Double Tm

Akt1 , Akt2tm1Rsg

12 12

Tm

Adenomatosis polyposis coli. Epidermal Tm

Apctm2Rak Tg(KRT14-cre)8Brn

18

Tm

Aqp2cph

15

S

Cdkn1atm1Led

17

Tm

Cdkn1b

6

Tm

Celsr1Crsh

15

ENU

Col5a2tm1Rmz

1

Tm

Col17a1 EdaraddCr

19 13

Tm S

Fuz Gab1tm1Thir

7 8

Tm Tm

Gab1tm1Wbm

8

Tm

Ikbkgtm1Mka

X

Tm

Aquaporin 2

Cyclin-dependent kinase inhibitor 1A (p21) Cyclin-dependent kinase inhibitor 1B Cadherin, EGF LAG seven-pass G-type receptor 1 (flamingo homolog, Drosophila) Collagen, type V, a2 Collagen, type XVII, a1 EDAR (Ectodysplasin-A recptor)associated death domain Fuzzy homolog (Drosophila) Growth factor receptor bound protein 2-associated protein 1(Gab1) Growth factor receptor bound protein 2-associated protein 1(Gab1) Inhibitor of kB kinase g (IKKg, NEMO)

Congenital progressive hydronephrosis

tm1Jro

Crash

tm1Shzu

Crinkled

Human keratin 8

Tg

Keratin complex 1, acidic, gene 16

Tg(KRT16)10Cou

Klotho

kl/kl

5

Tg

Kinase suppressor of Ras 1

Ksr1tm1Kole

11

Tm

Tg

At P4, HF development is delayed. Decreased number of HFs. Delay of HF development. At E18.5, HFs are still at developmental stage 1 or 2. At P10–12, short and misshapen vibrissae and short, shaggy pelage hairs. Hair bulbs are bent. Alopecia by 2 weeks of age. Ectopic HF-like structures in cornea, oral, salivary, and Harderian glands. Reduced zigzag hairs especially in heterozygotes. Large hair bulbs. Increased awl hairs. Misangled hair follicles at E18.5. Loss of planar polarization. Unusually deeply localized in the hypodermis hair bulbs. Partial hair loss. Phenotype identical to tabby, downless and IkBaDN mice. Retarded HF development. Delayed HF morphogenesis and thinner epidermis. At E17.5, retardation of HF development. Reduced number of HFs. At P5, sparse hair growth. Mouse model for Incontinentia Pigmenti. Only heterozygous mice are viable. Reduced number of HFs. Delay in development. Twisted and irregular HFs. Reduced and misoriented HFs. Short, curved and shaped like a sickle hair. Reduction in the number of hair follicles. At P10, fewer, disorganized, misoriented HFs with asynchronous growth. Separation of IRS from hair shafts. Short wavy hairs. Progressive hair loss.

S181

S182

S182

S73 S183

S184

S185

S186 S66 S187

S188 S189 S190 S191 S192

S193

S194

S195

S196

S197 S198

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13

Table 1 (Continued ) Mutant name

Symbol

Ch

Type

Abnormalities

Reference

Laminin a5

Lama5

tm1Jhm

2

Tm

S199–200

Laminin a5 Tm, transgenic Laminin a5 over-expressing mice, transgenic Laminin a5-a1 over-expressing mice Microtubule-associated protein 1B Nuclear receptor coactivator 6

Lama5tm1Jhm Mr5 Mr51

2

Tm Tg

Mtap1btm1Prop Ncoa6tm1Hhs

13 2

Tm Tm

Epidermal over-expression (bovine Keratin 5) of a non-degradable mutant of IkBa (inhibitor of kB). Pygopus2 RAS-related C3 botulinum substrate 1, epidermal Tm

K5-IkBaM

At E16.5, decreased hair germs by 50%. After grafting, failure of hair germ elongation. Poor association of dermal condensates under hair germs at E14.5 and E16.5. Rescue of hair abnormalities in Laminin a5 KOs by transgenic Laminin a5 and a5–a1 expression. Delay of HF development. In heterozygotes, reduction or total loss of HFs after wounding. Impaired hair growth. Alopecia. Hyperkeratosis.

Pygo2tm1.2Xdai Rac1tm1Brak Tg(KRT5-cre)5132Jlj

3 5

Tm Tm

RAS-related C3 botulinum substrate 1, epidermal Tm

Rac1tm1Djk K14-cre

5

Tm

V-raf-leukemia viral oncogene 1

Raf1tm1Zim

6

Tm

2 8

Tm

Tg

tm1Tyj

Retinoblastoma-like 1 (p107) Retinoblastoma-like 2

Rbl1 Rbl2tm1Tyj

Retroviral cyclin Serine (or cysteine) peptidase inhibitor, clade E, member 1 Stratifin Sclerostin domain containing 1

Tg(rv-CYCLIN)29Dlh Serpine1 Sfn Sostdc1tm1Nit

12

Tg Tm

Suppressor of tumorigenicity 14 (colon carcinoma) Suppressor of fused homolog (Drosophila) Tnf receptor-associated factor 6

St14tm1Bug

9

Tm

19

Tm

Traf6

2

Tm

Transient receptor potential cation channel, sub family V, member 3 Vang-like 2

Trpv3tm1.2Clph

11

Tm

Vangl2Lp

1

S

Wls K14Cre

3

Tm

Wntless, epidermal Tm

Sufu

tm1Rto

tm1Jino

Loop tail

deletion or of DNA isogenicity [45]. Another interesting development in the forward genetics field is transposon-based sitedirected mutagenesis [46]. In addition, the strategic and systematic generation of gene targeted mouse models across the entire genome has been initiated by different public and private entities [47,48]. 6. Selection and organisation of the presented mouse mutant tables Thus, an-ever growing number of genes responsible for HF morphogenesis, function and/or cycling has been identified by closely investigating the phenotypes of genetically engineered mice (GEM), spontaneous mutant mice and positional cloning. Mostly due to the detection of novel proteins expressed in skin and HFs, the number of mice exhibiting HF abnormalities has more than doubled

30% less HFs. Progressive hair loss beginning at 1 week. At P9, kinked HFs with constrictions. Thick hair bulbs. At P14, defective HFs with no clear hair bulbs. Abrupt end of IRS and ORS. Rudimentary hair follicles, absence of hairs on the skin surface. At birth, underdeveloped, less well organized HFs. Reduced HFs. Retardation of HF development. In skin grafts, increased hairs, multiple HFs sharing a unique hair channels, twisted HFs, multiple follicular keratin-filled cysts. Reduced number of HFs. Delayed HF morphogenesis.

Tg Tg

Tg

Reduced HF density. Ectopic HFs without change in HF cycling. At birth, fewer HFs. Retardation of HF development. In heterozytotes, ventral hair loss. Identical hair phenotype to tabby, downless, crinkled and IkBaDN mice. HFs were gently curved and pointed in different directions with variable angles. Mis-angled hair follicles at E18.5. Loss of planar polarization. Complete absence of HF development.

S201

S202 S203

S204

S205 S206

S207

S208 S209

S210 S211 S212 S213 S214 S215 S216

S217

S187

S218

since our last overview has been published in 2001. Due to space limitations, in the current review we therefore had to omit mice with spontaneous mutations, in which the genes responsible for the HF phenotype remain unknown. Mutant mice which exhibit only abnormalities in HF pigmentation [49] or sebaceous gland abnormalities [50] have also been excluded from coverage. All the references given in the tables are listed in the file ‘‘Supplementary References’’. In cases in which it was not possible to find a mutant name in the website of Mouse Genome Informatics (http://www.informatics.jax.org/), only the name of the gene is listed in the tables. Numerous GEMs display abnormalities of HF development (Table 1). For practical purposes, we do not distinguish between abnormalities in HF induction, spacing and morphogenesis. In Table 2, GEMs which display distinct abnormalities of HF cycle entry of progression are listed.

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Table 2 Mouse mutants with reported abnormalities of hair follicle cycling. Abbreviations: Ch, chromosome; IRS, inner rooth sheath; ORS, outer rooth sheath; Tm, targeted mutation; Tg, transgenic; S, spontaneous; Rad, radiation induced; UN, unknown. Mutant name Soluble factors and receptors Activin A receptor, type Ib

Symbol

Ch

Type

Abnormalities

Reference

Acvr1btm1.1Gsu Tg(KRT14-cre)8Brn

15

Tm

Retarded catagen entry.

S219

Tg

Delay of hair regrowth after depilation at telogen. Homozygotes do not enter into the telogen until P22–23. Acceleration of catagen and shortening of hair shaft length. Catagen retardation. Failure of HFs to initiate the first postnatal hair cycle. Lack of proliferation in outer root sheath cells below the stem cell compartment and hair matrix cells. Loss of quiescent HF stem cell niche. Delay in catagen entry.

S220

Antisense CD44 antigen BarH-like homeobox 2

Barx2tm1Rsd

Brain derived neurotrophic factor

Tg(Bdnf)1Paus

Brain derived neurotrophic factor Bone morphogenetic protein 4

tm1Tbn

Bdnf Tg(BMP4)6Blh

2

Tm Tg

Bone morphogenetic protein receptor, type 1A Bone morphogenetic protein receptor, type 1A. Epidermal Tm Cholinergic receptor, muscarinic 4

Bmpr1afl/fl K14-Cre Bmpr1atm2Bhr KRT14-cre Chrm4tm1Jwe

14 14

Tm Tg Tm

2

Tm

Delta-like 1

Dll1

17

Tm

EGF-like repeats and discoidin I-like domain 3 Estrogen receptor 2 (b)

Edil3

13

Tg

Esr2tm1unc

12

Tm

Estrogen receptor 1 (a) Estrogen receptor 2 (b)

Esr1tm1Ksk Esr2tm1unc

10 12

Tm Tm

Estrogen receptor 2 (b)

Esr2tm1unc

12

Tm

Fibroblast growth factor 5

Fgf5tm1Mrt

5

Tm

9

Tm Tg

Fibroblast growth factor 5

angora

Fgf5go

5

S

Fibroblast growth factor 5

Angora-Y

Fgf5goY

5

S

Fgf18tm1Tri Tg(KRT5cre)1Tak Gfra1tm1Jmi

18

Tm Tg

19

Tm

Gfra2tm1Msa

14

Tm

Ifngtm1Yiw

10

Tm

Fibroblast growth factor 18 Glial cell line derived neutrophilic factor family receptor a-1(GFRa-1) Glial cell line derived neutrophilic factor family receptor a-2(GFRa-2) Interferon g

Interleukin 6

Tg(Il6)1Efu

Jagged 1, epidermal Tm

Jag1 K5Cre

2

Tm Tg

Jagged 1 Catenin (Cadherin associated protein) b1 (Stabilised b catenin)

Jag1 K14DN-bcateninER

2

Tm Tg

Nerve growth factor Nerve growth factor receptor (p75) Neurotrophin 3

Tg(Ngf)47Kma Ngfrtm1Jae Ntf3tm1Jae

11 6

Tg Tm Tm

Neurotrophin 3 Neurotrophin 5 (4) Prolactin receptor

Tg(Ntf3)1Kma Ntf5tm1Jae Prlrtm1cnp

7 15

Tg Tm Tm

Retinoid X receptor a, epidermal Tm

Rxratm2Ipc Tg(KRT14-cre)1Ipc

2

Tm

Transforming growth facor b1 Transforming growth facor b1

Tgfb1tm1Doe Tgfb1

7 7

Tm Tm

Tg

S221 S222 S222 S223

S224 S7

At P17, delay in catagen development. Prolonged telogen. At 5 weeks, delayed entry into the first postnatal anagen. Early hair growth after depilation.

S225

17b-Estradiol fails to inhibit orchidectomy-induced anagen initiation. 17b-Estradiol fails to inhibit orchidectomy-induced anagen initiation. Accelerated catagen development at P19. AnagenVI extended and initiation of catagen delayed. 50% longer hair than that of wild types. Prolonged anagen, resulting in production of unusually long hair. AnagenVI extended by 3 days and initiation of catagen delays. Prolonged anagen. All hair types are longer. Short telogen in keratinocytespecific Fgf18 deficient mice. Accelerated catagen in heterozygotes. Accelerated catagen.

S228

At 5 weeks, HFs still at anagen. Hair loss in the dorsal and occipital area begininng at 6 weeks. Retarded hair growth possibly due to retardation of hair cycle. Progressive hair loss beginning at 5 weeks of age. At 5 weeks of age still in telogen. Seven and a half weekold mice are bald. Lack of anagen induction or HF de novo formation even in the presence of stabilized b-catenin expression. Acceleration of catagen. Catagen retardation. Catagen retardation in heterozygotes. Precocious catagen development. Catagen retardation. Accelerated hair cycling. Longer and coarser hairs. Impaired anagen initiation after depilation. Alopecia observed 6-7 weeks after tamoxifen treatment. Delay in catagen entry. Inhibition of telogen HFs to re-enter anagen.

S236

S226 S227

S228

S229 S230

S231–233

S233 S234 S235 S235

S237 S238

S238

S239 S239 S240 S240 S222 S241 S242

S243 S244

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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Table 2 (Continued ) Mutant name

Symbol tm1Hyn

Ch

Type

Abnormalities

Reference

2

Tm Tg

At P19, delay in catagen initiation. After depilation, delay in anagen entry. Failure of transition from telogen to anagen. Failure of transition from telogen to anagen. Forced expression of RANK led to a precoccious anagen entry. At day P19, delay in catagen entry.

S245 S245

Accelerated hair regrowth after depilation. Nearly total hair loss by 8 months. Impairment of hair cycle initiation when anagen is induced by depilation at P18. Progressive hair loss begininng at 4 weeks. A human VDR transgene under the control of K14 promoter restores normal hair cycling in VDR null mice. A VDR transgene with a mutation in the hormone-binding domains restores normal hair cycling in VDR null mice. And a VDR transgene with a mutation in the activation domain results in a partial rescue of hair cycling in VDR null mice. A human VDR transgene under the control of K14 promoter restores normal hair cycling in VDR null mice. Short hair, premature onset of catagen.

S248

Thrombospondin 1 Thrombospondin 1

Thbs1

Tumor necrosis factor (ligand) superfamily, member 11 Tumor necrosis factor superfamily, member 11 Tumor necrosis factor superfamily, member 11 Transient receptor potential cation channel, subfamily V, member 1 Vascular endothelial growth factor, epidermal overexpression. Vitamin D receptor

Tnfsf11tm1Pngr

14

Tm

Tnfsf11atm1.1Pngr

1

Tm

Tg(KRT14Vegfa)3Dtm Vdrtm1Ska

5

Tm

Vitamin D receptor

Vdrtm1Mbd

5

Tm

Vitamin D receptor

Vdrtm1Mbd K14-VDR

5

Tm Tg

Vitamin D receptor

Vdrtm1Mbd K14-VDR

5

Tm Tg

Vitamin D receptor

Vdrtm1Mbd K14-VDR

5

Tm Tg

S100A8-Tnfsf11a Trpv1

Wingless-related MMTV integration site 3 (Wnt3) Transcription factors Aryl hydrocarbon receptor nuclear translocator-like Catenin (Cadherin associated protein) b1, dermal Tm

tm1Jul

Tg 11

Tm Tg

Tg

Tg(Wnt3)7Gsb

S246 S246 S247

S249–250

S251 S252

S253

S254

S255

Arntltm1Bra

7

Tm

Delayed anagen progression.

S256

Ctnnb1, Tm CorinCre: Cor-cre

9

Tm

Lack of b-catenin in the dermal papilla results in absence of auchene hairs. No regeneration of HF from stem cells. Dramatic shortening and thinning of HFs. Role in stem cell activation. Continuous activation of b-catenin in telogen phase results in induction of an aberrant exaggerated anagen. Transient activation produces a normal anagen. B-catenin required for telogen-anagen transition. At P55, precocious entry into anagen. De novo HF morphogenesis in the interfollicular epithelium. Expression of stabilized b-catenin after 7days of 4OHT (tamoxifen) treatment induces anagen in existing HF and new HFs in IFE, including the paws. Delayed progression into the anagen. Premature disruption of hair cycle and discharge of immature HF. Lack of acid keratin expression. Dysregulation of regression process in catagen (DP remains distant from bulge), failure of regeneration and eventually complete hair loss. Hr controls timing of WNT signaling, which is required to initiate anagen. Retardation of anagen onset. Progressive hair and vibrissae loss beginning at 6 weeks of age. Enlarged and swollen bases of plucked HFs. Epitheloid cysts derived from HFs.

S257

Catenin (Cadherin associated protein) b1 (Activated b catenin)

K5/S33Yb-cateninER

Tg

Catenin (Cadherin associated protein) b1 (Stabilised b catenin)

K14-DNb-catenin

Tg

Catenin (Cadherin associated protein) b1 (Stabilised b catenin)

DNb-cateninER

Tg

Circadian locomotor output cycles kaput

Clocktm1.1Rep

5

Tm

Forkhead box N1

Traveling wave

Foxn1tw and Foxn1nu/nu

11

S

Hairless

Hairless

Hrhr

14

S

Lymphoid enhancer binding factor-1, absence of b-catenin binding domain

S246

Krt14DNLef1

Tg

S258

S259

S260

S256 S261–262

S263–277

S278

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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16 Table 2 (Continued )

Mutant name

Symbol

Ch

Type

Abnormalities

Reference

Tg

Alterations in hair cycle progression after normal initiation. Differentiation of HF stem cells into HF keratinocytes is disturbed. They differentiate into sebocytes, producing large cysts filled with oil. In Lhx2 null skin grafts: precocious anagen entry due to a shortened resting phase. At 11 weeks after transplantation, reduced numbers of label retaining cells (HF stem cells). Lack of differentiation and maintenance of HF stem cells. Accelerated wound-induced anagen development in heterozygous mice. Conditional deletion of Med1 in keratinocytes leads to a precoccious entry into catagen at P17. Shortened anagen. Premature and prolonged catagen. Precocious exogen. Cyclic alopecia, starting at P14. Reason: Expression of acidic keratins may be regulated by Msx2, together with Foxn1. Prolonged anagen, similar to angora mice. However, equally hair loss at a later time point (P18-P30) than Msx2tm1Rilm. Hair loss beginning at 14 days of age due to a premature catagen entry. Premature HF stem cell activation, leading to precocious follicle growth. Disruption of stem cell quiescence by aberrant expression of CDK4. Delayed entry into anagen after depilation. At 1-3 months of age, hair loss. Epidermal cysts derived from HFs. Delay in telogen to anagen transition. Lack of bulge stem cell proliferation during telogenanagen transition. At 3 months, obvious progressive hair loss. During catagen, HF fail to regress and persist in an abnormal anagen. Less TUNEL-positive cells. Same as in single Smad4 KOs, but much more intensive. This suggests synergy between Smad4 and Pten. Second anagen is not observed, and mice remained in telogen stage, even at P35. Normal first hair cycle. Retardation of hair cycling. Sparse hairs. Defective anagen phase induction: 3-4 weeks after tamoxifen injection, patchy hair loss and little or no hair growth after depilation. Short hairs. After activation of TCF3 (inhibitor of WNT signaling) expression by doxycycline at P1, lack of anagen entry and degeneration of HFs, because HF stem cells are not activated. TCF3 is required for maintaining HF stem cells in quiescence. At day 18 after depilation, HFs are still in catagen I-II. Retardation of catagen. Reduced number of apoptotic cells. At P19, retarded catagen entry.

S279

Lymphoid enhancer binding factor-1, absence of b-catenin binding domain

K14–DNLef1

LIM homeobox protein 2

Lhx2tm1Dra

2

Tm

LIM homeobox protein 2

Lhx2tm1Dra

2

Tm

Mediator complex subunit 1

Med1tm1Jkr

11

Tm

Homeobox, msh-like 2 (Msx-2)

Msx2tm1Rilm

13

Tm

Homeobox, msh-like 2 (Msx-2) Fibroblast growth factor 5

Msx2tm1Rilm Fgf5go(angora)

13 5

Tm S

Homeobox, msh-like 2 (Msx-2)

Tg(Msx2)1Rem

13

Tm

Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1

Nfatc1tm1Glm K14Cre

18

Tm Tg

Nuclear factor I/C

Nfictm1Rmg

10

Tm

Rbpj Nes-Cre Runx1Fl/Fl K14-Cre

5

Tm

16

Tm

Smad4co/co K5-Cre

18

Tm

Smad4co/co K5-Cre Ptenco/co K5-Cre;Stat3flox/

18 19

Tm Tm

11

Tm

Stat5btm1Hwd

11

Tm

Taf4lox/lox K14-Cre-ERT2

2

Tm

Transcription factor 3 (TCF3), epidermal over-expression of TCF3

TRE-mycTcf3 K14-rtTA

6

Tm

Transformation related protein 53

Trp53tm1Tyj

11

Tm

Krt14tm1(cre)Wbm Miz1lox/lox

4

Tm

Recombination signal binding protein for immunoglobulin kJ region Runt related transcription factor 1 Epidermal Tm

SMAD4, epidermal Tm

SMAD4, epidermal Tm Phosphatase and tensin homolog Signal transducer and activator of transcription 3 (Stat3). Epidermal Tm Signal transducer and activator of transcription 5B TAF4a RNA polymerase II, TATA box binding protein (TBP)-associated factor (TAF4). Epidermal Tm

Zink finger and BTB domain containing 17 (Miz1, Zbtb17) Enzymes

f/f

S110

S280

S281

S282

S282

S112

S283

S284 S285 S286

S287

S288

S289

S290 S291

S292

S293–294

S295

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Table 2 (Continued ) Mutant name

Symbol

Thymoma viral protooncogene 1

Akt1

Caspase 3 Diacylglycerol O-acyltransferase 1

Krt14-CreER MosiCasp3 Dgat1tm1Far

Dicer1, ribonuclease type III Drosha, ribonuclease type III Heparanase

Mitogen-activated protein kinase kinase kinase 5 Matrix metallopeptidase 14 (membrane-inserted) Phospholipase A2, group X

Ch

Type

Abnormalities

Reference

Tg

New hair growth in telogen after Akt activation. Ruffled and shaggy hairs. Large HFs. HF stem cell depletion.

S296

8

Tm

15

Tm

Dicer1tm1Smr Droshatm1Litt Hpse

12 15

Tm Tm Tg

Map3k5tm1Hijo

10

Tm

Mmp14tm1Hbh

14

Tm

Actb-Pla2g10 tm2Pst

Tg

Protein O-fucosyltransferase 1 Protein phosphatase 3, regulatory subunit B, a isoform (calcineurin B, type I) Prostaglandin-endoperoxide synthase 2

Pofut1 Ppp3r1tm2Grc Tg(KRT5-cre/ PGR)1Der Tg(K5-Ptgs2)19Kmd

2 11

PTK2 protein tyrosine kinase 2

Ptk2tm1Lfr Tg(KRT1-5cre)5132Jlj Terctm1Rdp

15

Tm

3

Tm

3 8

Tm Tm Tg

Telomerase RNA component

Telomerase RNA component Werner syndrome homolog (human) Telomerase reverse transcriptase Telomerase reverse transcriptase Telomerase RNA component Adhesion molecules Claudin 6 Gap junction protein, a1

Terctm1Rdp Wrntm1Lgu tetop-TERT actinrtTA tetop-TERT actinrtTA Terctm1Rdp Cldn6 Gja1m1Jnt

Tm Tm

Tg

3

Tg Tm

10

Tg ENU

Intercellular adhesion molecule 1 (ICAM-1) Integrin a3

Icam1tm1Bay Icam1tm1Jcgr Itga3tm1Jak

5

Tm

11

Tm

Integrin b6

Itgb6tm1Des

2

Tm

Junction plakoglobin

Tg(JUP)4Pac

Others RhoGTPase activating protein 1

Tg

Arhgap1tm1Yizh

2

Tm

Ataxia telangiectasia and Rad3 related

Atrtm1Bal Tg(UBC-cre/ ESR1)1Ejb

9

Tm

B-cell leukemia/lymphoma 2 (Bcl-2)

Bcl2tm1Tsu

1

Tm

B-cell leukemia/lymphoma 2 (Bcl-2)

Tg(BCL2)1Tsk

Tg

Bcl2-like (Bcl-xL)

Tg(BCL2L1)1Cbt

Tg

CD34 antigen

Cd34tm1Szk

1

Tm

Patchy alopecia at different locations after 9 weeks of age. Failure of catagen entry. Failure of catagen entry. At P16, delayed catagen entry. Enhanced hair regrowth after chemotherapy-induced hair loss. Delay of wounding-induced anagen initiation. Progressive patchy hair loss begininng at P50. Shortened anagen. Prolonged catagen and telogen. Delay in anagen reentry at P24. At P21–22, initiation of periodic hair loss. Lack of adherence of ORS to the hair shafts. At P11, precocious entry into the catagen. At 3–10 months, development of alopecia. Retarded catagen onset. From P7 until P17, sparse hairs. 25% fewer HFs. Alopecia in the third and sixth generation mice. Decreased percentage of hair follicles in anagen, increase in percentage of telogen follicles. 63% of 12–16-week-old mice show patchy hair loss. Rapid transition from telogen to anagen. Rapid transition from telogen to anagen.

S297 S298 S299 S299 S300

S301 S302 S303 S304 S305

S306

S307

S308

S309 S310 S310

At P16, precocious catagen. G60S mutation results in retarded anagen entry after depilation. Catagen acceleration.

S311 S312

At 45 days post grafting, increased numbers of telogen and catagen HFs. Retarded HF regression (catagen) after depilation. Precocious catagen development. Premature termination of the anagen.

S314

After removal of the dorsal hair by shaving, marked reduction of hair regeneration due to lack of anagen entry. 3–6 months after tamoxifen treatment, progressive hair loss. Delay in anagen progression after depilation. Degenerative HFs. Second hair cycle occurs later than normal at 5–6 weeks of age. Accelerated catagen progression. Increased alopecia, hair follicle dystrophy, and apoptosis after cyclophosphamide injection. Short hair with decrease in the duration of anagen and prolongation in telogen. Fgf-5 deficiency can reverse the Bcl-xLinduced phenotype. After TPA treatment, delay of entry into catagen.

S313

S315 S316

S317

S318

S319 S320

S321

S322

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18 Table 2 (Continued )

Mutant name Dishevelled 2, dsh homolog (Deosophila) Human papillomavirus type 16 E6/E7 papillomavirus oncogene ERBB receptor feedback inhibitor 1 Gasdermin A3

Symbol

Ch

Type

Abnormalities

Reference

Tg(Dvl2)7Gsb

Tg

S255

Tg(bK6-E6/E7)M8

Tg

Short hair, premature onset of catagen. Longer anagen and no telogen. Lower hair density. At P18, still in anagen. Large HFs. Scarring alopecia. Sparse coat develops at the end of first hair cycle. At P21, long follicles without regressing. Lack of auchene hairs. Dilated infundibulum plugged with cornified material. Hair loss begininng at 3–4 weeks. At 9–12 weeks of age, destruction of HFs. At about 4 weeks of age, hairs become sparse on the head and neck. After 6 weeks loss is progressive. Hair loss beginning at P23. At P27, protracted abnormal catagen. Hair loss beginning around 3 weeks of age. Defective anagen entry with activated Kras expression. Progressive hair loss. Slower progression through catagen. Cysts in HFs. After plucking only occasional entry into anagen. Reduced HF stem cells. At P15, early catagen induction. Short hairs evident at P15, P40. At P17, retarded catagen entry. 11–15 days after tamoxifen treatment, diminution of the hair bulb, degeneration of the infundibulum into cysts. At 4–6 months, abnormal abdominal hairs. Increased catagen II–III and anagen IV–V HFs. Mild alopecia. Block at the telogen. Loss of CD34 expression in anagen bulge cells. 6 days after depilation, all HFs remain in telogen.

Bare skin

Tg (K14-Errfi1) Gsdma3Bsk

11

Tg ENU

Gasdermin A3

Defolliculated

Gsdma3Dfl

11

S

Gasdermin A3

Denuded

Gsdma3Reden

11

S

Gasdermin A3

Reduced coat 2

Gsdma3Rco2

11

ENU

Gsdma3I359N

11

ENU

6

Tm

Gasdermin A3 v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog LIM domain binding 1

Latent transforming growth factor b binding protein 1 Melanoma antigen, family D, 1 RAS-related C3 botulinum substrate 1, epidermal Tm

Ldb1

Tg

Ltbp1

Tg

Rac1tm1Djk Tg(KRT14-cre/ Esr1)20Efu

X 5

Tm Tm

Serine (or cysteine) peptidase inhibitor, clade B (ovalbumin), member 13 T-cell lymphoma breakpoint 1

Serpinb13

Tcl1tm1Rso

12

Tm

Wiskott-Aldrich syndrome-like (human)

Wasltm2Sbs

6

Tm

Tg

S323 S324 S325

S326

S327

S328 S329 S330 S331

S332 S333 S334

S335

S336

S337

Table 3 Mouse mutants with reported abnormalities of hair structure. Abbreviations: Ch, chromosome; IRS, inner rooth sheath; ORS, outer rooth sheath; Tm, targeted mutation; Tg, transgenic; S, spontaneous; Rad, radiation induced; UN, unknown.

Soluble factors and receptors Ectodysplasin-A1 (EDA-A1)

Fibroblast growth factor receptor 2 Insulin-like growth factor binding protein 5 Lamin B receptor

Noggin

Mutant name

Symbol

Ch

Type

Abnormalities

Reference

Tabby

EdaTa6J, EdaTa, EdaTac

X

S

Altered ultrastructure of awl hairs. It is also suggested that zigzag hair ultrastructure is converted into awl ultrastructure resulting in almost the same HF numbers as in wild-type mice. Thin hairs. Reduced hair medulla most likely due to increased apoptosis. Short hair shafts. Reduced hair medulla.

S12

Structural abnormality of IRS and cuticle. Scant, short coat and short and coiled vibrissae. Impairment of hair shaft differentiation. Fine, short, wavy and twisted hairs, containing bulbous pertubations in the shafts. Improperly organized Henle’s layer. Medulla with fewer, disorganized trichohyalin granules. HF contained a core with large loosely packed cells, replacing the IRS.

S339

Ichthyosis

Fgfr2

Tg

Igfbp5

Tg

Lbric

1

Nog

S

Tg tm2Rko

Notch 1, epidermal Tm

Notch1 Tg(Msx2-cre)5Rem

2

Tm

Notch 1 Notch 2 Epidermal Tms

Notch1tm2Rko Notch2tm1Rko Tg(Msx2-cre)5Rem Notch 1

2 3

Tm

2

Tm

Notch 1

Thin, short and wavy hairs.

S338 S338

S340 S165

S165

S341

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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19

Table 3 (Continued ) Mutant name

Symbol

Ch

Type

Abnormalities

Reference

Wavy hairs and short, curly vibrissae and a diffuse pattern of alopecia. Defect in differentiation of the inner root sheath. Persistence of inner root sheath remnants in later stage of the hair cycle. Curly vibrissae and wavy hairs. Abnormal differentiation of the medulla and the cuticle. At 3–5 months, ORS hyperplasia due to abnormally high ORS cell proliferation.

S342

S102

Notch 1

Tg(Notch1)1Anc

Tg

Notch 1

Tg(Notch1)A3Rko

Tg

Patched 1. Companion cell layer Tm Transcription factors Distal-less homeobox 3. Epidermal Tm

Krt6a-Cre;Ptch1neo/neo

13

Tm

Dlx3tm2Mso Tg(KRT14-cre)Smr

11

Tm Tg

S343

S344

Forkhead box N1

Nude

Foxn1nu

11

S

Forkhead box N1 Forkhead box N1 Forkhead box N1

Nude St Louis Nude streaker Traveling wave

Foxn1nuStL Foxn1nustr Foxn1tw

11 11 11

S S S

Forkhead box N1 Forkhead box N1 Forkhead box N1. Over-expression under the involucrin promoter. Forkhead box N1. Cosmid over-expression of genomic FoxN1 clone. Forkhead box Q1

Nude Yurlovo

Foxn1nuY Foxn1tm1Tbo Tg(Hoxcn13)61Blb

11 11

S Tm Tg

Structural HF abnormalities already visible at P5. At P9, no apparent medulla. No development of hair bulbs and undifferentiated hair shafts. Multiple fractures and twist in hair shafts. Short and curly vibrissae. Abnormal globular aggregates in the IRS and hair shaft. Similar to nude mice. Similar to nude mice. Waves of traveling stripes with aberrant pigmentation along body. In wave front abnormal HFs with bent and coiled hair shafts. Similar to nude mice. Similar to nude mice. Wavy coat and curly whiskers.

Tg

Rescue of nude hair phenotype.

S351

Satin

Foxq1sa

13

Rad

S352

Forkhead box Q1

Satin, ENU1

Foxq1sae1

13

ENU

GATA binding protein 3

Gata3tm1Gsv

2

Tm

GATA binding protein 3. Epidermal Tm

Gata3tm3Gsv Tg(KRT14-cre)8Brn

2

Tm

Grainyhead-like 1

Grhl1

12

Tm

15

Tm

Tg(Foxn1)G2Hon

S345

S346 S347 S261

S348 S349 S350

Homeo box C13

Hoxc13

Homeo box C13

Tg(Hoxc13)61B1Awg

Avian musculoaponeurotic fibrosarcoma (v-maf) AS42 oncogene homolog V-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (avian) OVO homolog-like 1

Maftm1Mym

8

Tm

Thin hairs. Abnormal keratinization of hair shaft. Shiny hairs. Disorganized medulla cells. Lack of air spaces and cortical ridges in medulla. At E18.5, lack of IRS. In skin graft, lack of Huxley’s layer and IRS cuticle cells, short hair shafts. Thick ORS, absence of Huxley’s layer and IRS cuticle. Short and stubby hairs growing at a wide angle, often parallel to the skin surface. Sparse hairs. Clefts between ORS and IRS. Hair fracturs at the skin surface all over the body, resulting in complete alopecia. Lack of or irregular septum in cuticle, resulting in fracturing near the root. Thickened ORS. Kinked vibrissae. Irregularly patterned cuticle at E18.5.

Mafbtm1Jeng

2

Tm

Thin and irregularly patterned cuticles.

S358

Ovol1tm1Efu

19

Tm

S359

5

Tm

Kinks and/or intercellular splits within or along the hair shafts. Disrupted organization of IRS and cuticle layern. Cystic degeneration. At 6 months of age, 90% of the fragile zigzag hairs display much less pronounced bends with various bending directions. Less dense and ruffled hairs in adults. Much less-prominent bends in the auchenes and zigzags. Shorter zigzags with fewer and thickened bends. Abnoramal cuticle formation and missing interlocking structure between cuticle and IRS cuticle.

S361

tm1Mrc

tm1Hon

Rbpj

Recombination signal binding protein for immunoglobulin k J region Runt related transcription factor 1. Epidermal Tm

Runx1tm2Spe Tg(KRT5-cre)5132Jlj

16

Tm

Runt related transcription factor 3

Runx3tm1Yg

4

Tm

SRY-box containing gene 21

Sox21

14

Tm

Adam10tm2Psa K14-Cre

9

Tm

Enzymes A disintegrin and metallopeptidase domain 10

ColI-Cre

Tg

Destroyed HF with epidermal cyst formation.

S353

S354

S106

S355 S356

S357

S358

S360

S362

S288

S363

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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20 Table 3 (Continued )

Mutant name

Symbol tm1Prc

Ch

Type

Abnormalities

Reference

A disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 2 Deoxyribonuclease 1-like 2

Adamts2

11

Tm

At 2 months, less dense hairs with thinner hair shafts.

S364

Dnase1l2tm1Eckh

17

Tm

S365

Excision repair cross-complementing rodent repair deficiency, complementation group 2 Excision repair cross-complementing rodent repair deficiency, complementation group 2 Matrix metallopeptidase 9 Phospholipase A2, group X

Ercc2tm1Jhih

7

Tm

Ercc2tm2(ERCC2)Jhih

7

Tm

Mmp9tm1Tvu Pla2g10tm1Kiku

2 16

Tm Tm

2

Tg Tg Tm

Tnfaip3 K14-Cre

10

Tm

Indentations in hair cuticles. Hairs are less resistant to mechanical stress. Brittle hairs and nails like trichothiodystrophy. Reduced cysteinerich matrix proteins of the hair. From 3 monthsonwards, brittle and greasy hairs. Follicular dilation and sebaceous gland hyperplasia. Decreased width of the hair canal. Disorganized and small ORS vacuoles. Thin ORS. Scarse and curly whiskers at 3 weeks of age in bi-transgenic mice. Thin hairs with irregular torsions. Small cracks in the cuticle. Thin and fragile hairs with cuticle damages.

Cdh1 K14-Cre

8

Tm

S372

Cadherin 1 Epidermal Tm

Cdh1 Krox20-Cre

8

Tm

Desmoglein 3

Dsg3tm1Stan

18

Tm

Desmoglein 3

Dsg3tm1Stan

18

Tm

Dsg3bal

18

S

Dsg3balPas

18

S

At P10, hairs are short and fragile. By 1.5 months of age, misangled HFs. Distorted vibrissae. Adherens junctions between the companion layer and Henle layer, and between the Henle layer and the Huxley layer are missing. At P30, dorsal hairs became less shiny. Curly vibrissae. Reduction of intercellular tightness in the Huxley layer. Loss of cell adhesion (acantholysis) between the cells surrounding the telogen club and the basal layer of the outer root sheath epithelium. Rescue of Dsg3 deficient mice phenotype by the expression of Dsg1 transgene. Separation between the inner and outer root layer of the outer root sheath. Separation between the inner and outer root layer of the outer root sheath. Short hair shaft with a focal degeneration. Abnormal cornification of the matrix region with degeneration. Periodic nodules along the shaft resembling trichorrhexis Dishevelled, thinner and dull hairs. Altered medulla airspaces. Reduction of IRS length.

Plau Plaur

Plasminogen activator, urokinase Plasminogen activator, urokinase receptor Transglutaminase 3, E polypeptide

tm1.1Gvl

Tumor necrosis factor a-induced protein 3 Adhesion molecules Cadherin 1. Epidermal Tm

S366

S367

S368 S303 S369 S370 S371

S373

S374–375

S376

Desmoglein 3. One base pair insertion in Dsg3 Desmoglein 3

Balding

Desmoglein 4

Lanceolate hair

Dsg4lah

18

ENU

Desmoglein 4

Lanceolate hair-J

Dsg4lahJ

18

S

Pkp3tm1Fvr

7

Tm

AifmHq

X

S

Structural abnormality of hair shaft.

S383

Cdc42

4

Tm

S384

Cst6Ichq

19

S

At P14, no hair matrix, IRS, or hair shaft cells observed. Homozygotes fail to develop normal first hair coat. Few hairs emerge, and the short and thin hair shafts are surrounded by a collar of cornified cells. Hairs break easily. Striped hair coat resulting from areas of shorter and wrinkled hair shafts. HFs with dystrophic or absent inner root sheath. Premature separation of hair shaft from the inner root sheath. Abnormal keratinization.

Plakophilin 3

Others Apoptosis-inducing factor mitochondrion-assiated 1 Cell division cycle 42 homolog (S. cervisiae) Cystatin E/M

Harlequin

tm1Brak

Adenovirus truncated E1a

Phenylalkylamine Ca2+ antagonist (emopamil) binding protein Inositol1,4,5-triphosphate receptor 3 Keratin complex 2, basic, gene6 (Dominant negative) Keratin complex 2, basic, gene6 (C-terminal change) Sheep wool intermediate keratin

Tg(Av-E1A)901Gpd

tattered

EbpTd tm1Kmik

Itpr3

Tg(Krt2-6a)1Der

Tg

X

Rad

17

Tm Tg Tg

Tg(KRT2-9)1Grog

Tg

Loosely attached telogen HFs. Sparse keratin filaments. Collapsed keratin filaments in the outer root sheath. Disorganized appearance of outer root sheath. Vacuolization of ORS cells. Hairs break off near the skin surface.

S377–379 S377–379 S380

S381 S382

S385

S386

S387–388 S389 S390–391 S390–391 S392

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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21

Table 3 (Continued ) Mutant name Keratin 17

Symbol Krt17

tm1Cou

Ch

Type

Abnormalities

Reference

11

Tm

At P10, premature separation of the ORS and IRS from the hair shaft. Cytolysis and pyknotic nuclei in ORS. Break and rupture of the hair shafts. Massive apoptotic cells in hair bulbs. Curved vibrissae and wavy hair until about 4 weeks of age. Homozygotes have extremely curly hairs. Between 3 and 6 weeks of age wavy hairs pointing in different directions. At 5 weeks, curved and twisted HFs. Lack of uniform thickness and abnormal keratinization in IRS. Curly vibrissae and hairs with kinks and twists. Defective keratinization of Henle’s and Huxley’s layers. At P10, curly hairs with bends. Irregularly formed Henle’s and Huxley’s layers. Formation of large whorls by intermediate filaments in Henle’s layer. Rough coat developing at about P15. Focal distentions of the hair shafts associated with clusters of loose aggregates of round cells. Fractioning of the cuticle. Breakage of the shafts. Curly hairs. Thinner hair shafts. At P8, abnormal shape and orientation of HFs. At P20, smaller club with few club sheath cells attached. Reduction of anchoring protrusions in keratinized cells. Abnormally oriented and curved hairs. Loss of adhesion in the IRS, and between the IRS and hair shaft. Premature keratinization of IRS. Fragile hair shafts. Absence of regular cuticular separation. Wavy vibrissae at 2–3 days. Thinner hairs or alopecia. Hair shafts have pits, striations, and protrusions.

S393

Keratin 71

Caracul

Krt71Ca

15

S

Keratin 71

Directional caracul

Krt71Cad

15

S

15

S

CaRin

Keratin 71

Caracul Rinshoken

Krt71

Keratin 71

Reduced coat 3

Krt71rco3

15

ENU

Keratin 71

Reduced coat 12

Krt71Rco12

15

ENU

Krt75tm1Der

15

Tm

Waved 3

Ppp1r13lWa3

7

S

Repeated epilation

SfnEr

4

Rad

Serine peptidase inhibitor, Kazar type 5

Spink5tm1Hov

18

Tm

Serine protease inhibitor, Kunitz type 1 SV40 T antigen

Spint1tm1HK

2

Tm

Keratin 75

Protein phosphatase 1, regulatory (inihibitor) subunit 13 like Stratfin

Tetratrcopeptide repeat domain 7

Tg Flaky skin

Ttc7fsn

17

S

S394 S395 S396

S397

S398

S399

S400 S401

S402

S403 S404 S405

Table 4 Mouse mutants with reported secondary hair abnormalities as a result of extrafollicular events/pathology. Abbreviations: Ch, chromosome; IRS, inner rooth sheath; ORS, outer rooth sheath; Tm, targeted mutation; Tg, transgenic; S, spontaneous; Rad, radiation induced; UN, unknown; ENU, ethyl-nitrosourea induced.

Soluble factors and receptors Fas antigen

Mutant name

Symbol

Ch

Type

Abnormalities

Reference

Lymphoproliferation

Faslpr

19

S

MRL/lpr mice lose hairs with increasing dermal T-cell infiltration. Hair loss due to dermal mononuclear cell infiltration. Hair loss due to lymphocyte and neutrophil infiltration. Hair loss due to T cell infiltration. Hair loss due to lymphocyte and mast cell infiltration. Hair loss due to inflammatory cell infiltration including mast cells. Hair loss due to T lymphocyte and monocyte infiltration. Hair loss due to T lymphocyte infiltration.

S406–407

Interleukin 1a

Tg(Il1a)1.1Tsk

Tg

Interleukin 2

Il2

Tg

Interleukin 7 Interleukin 15

Tg Tg

Interleukin 31

Il7 Tg(H2-D-Il15) 3304Clgr Il31

Interferon g

Ifng

Tg

Transforming growth factor b1 Transcription factors E2F transcription factor 2

Tg

Tgfb1tm1N

7

Tm

E2f2tm1Zubi

4

Tm

11

Tm

tm1.1Mrc

Homeo box B8

Hoxb8

Interferon regulatory factor 2

Irf2tm1Mak

8

Tm

Pancreatic and duodenal homeobox 1

Pdx1tm1Cvw

5

Tm

Inflammatory infiltration. Hair loss in the aged mice. Excessive hair grooming leads to hair removal. Lymphocytic infiltration in the dermis. Progressive hair loss begininng at 8 weeks of age. Malnutrition.At P6.5, very little fur.

S408 S409 S410 S411 S412 S413 S414 S415 S416 S417

S418

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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22 Table 4 (Continued )

Mutant name

Symbol

Ch

Type

Abnormalities

Reference

Relb

7

Tm

Alopecia and hyperkeratosis at 4–10 weeks of age due to inflammatory cell infiltrations in the skin. Mouse model for atopic dermatitis.

S419

Agatm1Vk

8

Tm

Aspartylglycosaminuria. At 5 months of age, hairs became disheveled. Arginine deficiency. Delay of HF morphogenesis. Distortion of HFs. Keratin plugs clogging the hair canals. Resembles maple syrup urine disease. Thin and scant hairs. Hyperhomocysteinemia. At 3 months, thin hairs on the head. Increased number of HFs on the back. Double mutants showed severe dilatation of HFs.

S420

tm1Brv

NfkB RelB

Enzymes Aspartylglucosaminidase Arginase 1, liver

Tg(Fabp2-Arg1)1Wla

Tg

Bcat2m1Ytc

7

ENU

Cbstm1Unc

17

Tm

Excision repair cross-complementing rodent repair deficiency, complementation group 2. Xeroderma pigmentosum, complementation group A Helicase, lymphoid specific

Ercc2tm2(ERCC2)Jhih Xpatm1Hvs

7 4

Tm Tm

Hellstm1Rarc

19

Tm

Iduronate 2-sulfatase

Idstm1Muen

X

Tm

8

Tm

Branched chain aminotransferase 2, mitochondrial Cystathione b-synthase

Mutation 1, Yuan-Tsong Chen

tm1Cgn

Inhibitor of kappaB kinase beta (IKK2), epidermal Tm

Ikbkb K14-Cre

Lipase, member H

Lipid defect

Liphlpd1

Lipin1

Fatty liver dystrophy

Lpn1fld

5,10-Methylentetrahydrofolate reductase NAD(P) dependent steroid dehydrogenase-like. Mutation in Nsdhl gene. NAD(P) dependent steroid dehydrogenase-like. Mutation in Nsdhl gene. Polymerase (DNA directed) g

12

S

Mthfr

4

Tm

Bare patches 1 Harwell

NsdhlBpa1H

X

Rad

Striated 1 Harwell

NsdhlStr1H

X

Rad

Polgtm1.1Lrsn

7

Tm

Polgtm1Tprol

7

Tm

Ptpn6me

6

S

6

S

tm1Rzn

Polymerase (DNA directed) g Protein tyrosine phosphatase, non receptor type 6 Protein tyrosine phosphatase, non-receptor type 6 N-sulfoglucosamine sulfohydrolase (sulfamidase) Adhesion molecules Catenin (cadherin associated protein), d1. Epidermal Tm Integrin b6

Motheaten

mev

Viable motheaten

Ptpn6

Mucopolysaccharidosis IIIA

Sgshmps3a

11

S

Ctnnd1tm1Abre Tg(KRT14-cre)1Efu

2

Tm

Itgb6tm1Des

2

Tm

Itgb2tm1Bay Itgb2tm2Bay

10

Tm

Gsdma3Ae

11

ENU

Integrin b2 (CD18)

Others Gasdermin A3

Tg

Alopecia and excoriation

Human apolipoprotein C1

Tg(APOC1)1Lmh

Tg

Inhibitor of kappa B kinase gamma (IKKg/NEMO)

Ikbkgtm1Mka

X

Tm

Lamin A

Lmnatm2Stw

3

Tm

Nuclear factor of k light chain gene enhancer in B-cells inhibitor z Secretogranin V

Nfkbiztm1Mamo

16

Tm

Scg5tm1Led

2

Tm

Hypomethylation of DNA. At P17, hair loss and graying. Resembling Hunter syndrome. At 3–4 months of age, development of alopecia. With lymphocyte infiltration, resembling psoriasis. At P8, hair loss with widespread scaling. Problem with fat metabolism. At P3, retarded HF development. Problem with fat metabolism. Retarded and abnormal hair growth. Hyperhomocysteinemia. Sparse hairs appear 5 days later than wild-type. Hyperkeratosis involving hair follicles resembling nonbullous ichthyosis. Foci of alopecia after 5 days of age. Hyperkeratosis involving HFs resembling nonbullous ichthyosis.

S421

S422 S423

S424

S425 S426 S427

S428 S429 S430 S431–432

S432–433

Varying alopecia initiated at about 25 weeks as a sign of premature aging. At 9 months of age, hair loss and graying develops as a sign of premature aging. Disruption of HFs after the neutrophilic infiltration. The disease progresses more slowly than that of motheaten mice with neutrophilic infiltration. Resembles Sanfilippo syndrome. At 6–7 months, hairs became scruffy.

S434

Lymphocytes infiltration. Large patches of hair loss, which were rescued by dexamethasone treatment. Juvenile baldness associated with infiltration of macrophages into the skin. Hyperkeratosis and diffuse lymphocyte infiltration in the dermis. Alopecia at a mean age of onset of 11 weeks.

S441

Immune-mediated destruction of bulge stem cells. Inflammatory cells in the dermis. Atrophic sebaceous glands, thin hair-coat, thickened epidermis. In females at P10, sparse hair growth accompanied by neutrophil infiltration. Mouse model for incontinentia pigmenti. Resembles progeria. Reduced number of HFs. Progressive hair loss beginning at 4–8 weeks of age in the periocular skin with mononuclear infiltration. Resembling Cushing’s syndrome. Thin hairs. Regional alopecia.

S435 S436–438 S439

S440

S442 S443

S444 S445

S446

S447 S448

S449

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001

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Table 4 (Continued ) Mutant name Solute carrier family (zinc transporter), member 4. Nonsense mutation in Slc30a4 gene Survival motor neuron 1. Human surviaval motor neuron 2

Lethal milk

Symbol Slc30a4

lm

Smn1tm1Hung Tg(SMN2)2Hung

Table 3 summarizes mice with abnormalities of hair fiber ultrastructure. Since several mutant mice also have hair abnormalities as a result of extrafollicular events, they are listed separately in Table 4. 7. Published hair phenotype descriptions: cautionary comments Note that analysis and description of hair phenotypes differs greatly between the different laboratories, and first reports of a hair phenotype often are so cursory that they need to be interpreted with great caution. In many cases, the hair phenotype was only an – often unexpected – chance observation, with hair research being well outside of the primary interest and expertise of the reporting laboratory. Therefore, one or more of the four routine mistakes outlined above often were made in the initial hair phenotype description, and the hair phenotype of many GEM remains to be subjected to professional, quantitative hair phenotype analysis. In consequence, initial hair phenotype descriptions should not be accepted uncritically. Moreover, some published hair phenotype descriptions are rather superficial or vague, making it difficult to correctly sort them into one of the 4 phenotype categories reflected by the 4 tables shown in the review. More professional future hair phenotype analyses of these mutants may thus necessitate corresponding corrections. Another note of caution applies to published claims that a given mouse mutant has ‘‘no hair phenotype’’. Most newcomers to the field tend to expect that a hair phenotype is only present if there is visible hair loss or appreciable changes in hair shaft length, structure and/or pigmentation. This is an erroneous assumption: Even substantial changes in the speed of HF morphogenesis and/or the HF cycling characteristics can go along without any macroscopically detectable changes in the murine fur coat. Given the enormous frequency of HF-associated changes in professionally analysed GEMs, in which a HF phenotype was entirely unexpected, it is advisable to follow the golden rule ‘‘Every mouse mutant has a hair phenotype – until ruled out by quantitative histomorphometry of HF morphogenesis [6] and cycling [5,7].’’ Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jdermsci.2012. 10.001. References [1] Paus R, Cotsarelis G. The biology of hair follicles. N Engl J Med 1999;341:491–7. [2] Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a dynamic miniorgan. Curr Biol 2009;19:R132–42. [3] Nakamura M, Sundberg JP, Paus R. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: annotated tables. Exp Dermatol 2001;10:369–90. [4] Sundberg JP. Handbook of mouse mutations with skin and hair abnormalities: abnormal models and biomedical tools. Boca Raton Florida: CRC Press; 1994. [5] Sundberg JP, Peters JM, Paus R. Analysis of hair follicles in mutant laboratory mice. J Investig Dermatol Symp Proc 2005;10:264–70.

Ch

Type

Abnormalities

Reference

2

S

Alopecia due to zinc deficiency.

S450–451

13

Tm

Resembles spinal muscular atrophy. At P10, delay of HF development.

S452

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Motonobu Nakamura (MD, PhD) is Professor at Department of Dermatology in University of Occupational and Environmental Health, Japan. He graduated from Kyoto University, Japan and received his MD degree in 1991. He received his PhD in 1997 at Kyoto University. In 2000–2002, he served as Visiting Researcher under Prof. Ralf Paus at Department of Dermatology, University Medical Center Hamburg-Eppendorf, Germany. He moved to University of Occupational and Environmental Health as the Assistant Professor in 2008 and became Professor in 2012. His research interest includes pathomechanisms of alopecia.

Please cite this article in press as: Nakamura M, et al. Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: An update. J Dermatol Sci (2012), http://dx.doi.org/10.1016/j.jdermsci.2012.10.001