The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis

Seminars in Cell & Developmental Biology 16 (2005) 612–622

Review

The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis Dan Luo a,1 , Val´erie M. Renault a,1 , Thomas A. Rando a,b,∗ a

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5235, USA b GRECC and Neurology Service, VA Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, USA Available online 8 August 2005

Abstract The Notch signaling pathway is an evolutionarily conserved pathway that is critical for tissue morphogenesis during development, but is also involved in tissue maintenance and repair in the adult. In skeletal muscle, regulation of Notch signaling is involved in somitogenesis, muscle development, and the proliferation and cell fate determination of muscle stems cells during regeneration. During each of these processes, the spatial and temporal control of Notch signaling is essential for proper tissue formation. That control is mediated by a series of regulatory proteins and protein complexes that enhance or inhibit Notch signaling by regulating protein processing, localization, activity, and stability. In this review, we focus on the regulation of Notch signaling during postnatal muscle regeneration when muscle stem cells (“satellite cells”) must activate, proliferate, progress along a myogenic lineage pathway, and ultimately differentiate to form new muscle. We review the regulators of Notch signaling, such as Numb and Deltex, that have documented roles in myogenesis as well as other regulators that may play a role in modulating Notch signaling during satellite cell activation and postnatal myogenesis. © 2005 Elsevier Ltd. All rights reserved. Keywords: Myogenesis; Satellite cell; Notch; Numb; Deltex

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Notch and myogenic differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Notch signaling in satellite cell activation and postnatal myogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulators of Notch signaling: potential mechanisms of regulation of postnatal myogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Numb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Background, structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Cellular functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Molecular mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Deltex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Background, structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Cellular functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3. Molecular mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

613 613 614 616 616 616 616 617 617 617 618 618

Abbreviations: Arf6, ARF ribosylation factor 6; bHLH, basic helix-loop-helix; CSL, CBF1, Supressor of Hairless, Lag-1; DSL, Delta, Serrate, Lag-2; E(spl), Enhancer of Split; JNK, jun N-terminal kinase; MADS, MCM1, agamous, deficiens, serum response factor; MEF2, myocyte enhancer factor 2; MRF, myogenic regulatory factor; NICD, Notch intracellular domain; PRR, proline-rich region; PTB, phosphotyrosine binding; SCF, Skp1–Cullin–F-box; Su(dx), Suppressor of Deltex; Su(H), Supressor of Hairless ∗ Corresponding author. Tel.: +1 650 858-3976; fax: +1 650 858 3935. E-mail address: [email protected] (T.A. Rando). 1 These authors contributed equally to this review. 1084-9521/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcdb.2005.07.002

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

4.3. 4.4.

5.

ITCH, Su(dx) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sel-10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. Ubiquitination and proteasome degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Dishevelled . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Notch signaling plays an important role in tissue morphogenesis both during development and during postnatal regeneration of skeletal muscle, regulating such diverse processes as proliferation, differentiation, and cell fate decisions [1]. The focus of this review is to summarize the current evidence of the role of Notch in postnatal myogenesis, to focus on how regulation of this pathway guides effective muscle regeneration and repair, and finally to discuss specific regulators of Notch signaling that may be critical for the myogenic program. The Notch signaling pathway is an evolutionarily conserved pathway that plays a critical role in tissue development in organisms ranging from nematodes to mammals. The canonical Notch signaling pathway is initiated by the binding of one of the DSL (named for Delta, Serrate, and Lag-2) family of ligands to the one of the members of the Notch family of transmembrane receptors [2,3]. Ligand binding leads to sequential enzymatic cleavage of the Notch receptor and release of the active form of the protein, also known as NICD (Notch intracellular domain), into the cytoplasm. NICD then translocates to the nucleus where it binds members of the CSL (named for CBF1 (also known as RBP-J), Supressor of Hairless (Su(H)), and Lag-1) family of transcriptional repressors, converting them to transcriptional activators [1,4–6]. The targets of these transcription factors are typified by the Enhancer of Split (E(spl)) complex in Drosophila and the Hes and Hey genes in vertebrates [1,4–6]. In Drosophila development, the basic helix-loop-helix (bHLH) proteins encoded by the E(spl) complex serve to inhibit differentiation programs, such as those necessary for neurogenesis and myogenesis [1].

2. Notch and myogenic differentiation Myogenesis, whether during development or during postnatal regeneration, involves the expansion of mononucleated progenitor cells, their progression along a myogenic lineage pathway to become fusion-competent myoblasts, their migration and alignment, and finally their differentiation. The differentiation of myoblasts results in both profound morphological and biochemical changes. Morphologically, myoblasts fuse to form multinucleated myotubes which further develop to become the myofibers of mature skeletal muscle. Biochemically, myogenic differentiation is charac-

613

618 619 619 619 619 619 619

terized by the coordinate upregulation of genes encoding proteins that subserve the fundamental functions of mature muscle, proteins such as myosin, sarcomeric actin, and creatine kinase. This biochemical differentiation is regulated by two families of transcription factors: (i) the bHLH myogenic regulatory factors (MRFs), which include MyoD, myogenin, Myf-5, and MRF4; and (ii) myocyte enhancer factor 2 (MEF2) proteins, which belong to the MADS (MCM1, agamous, deficiens, and serum response factor)-box family [7,8]. Members of both families are able to bind directly DNA to activate transcription. The binding of each factor to its DNA binding site helps to recruit and stabilize the binding of the other factor via protein–protein interactions [9]. This cooperative activation of transcription is facilitated by the close proximity and coordinated positioning of the binding sites for MRFs and MEF2 in promoters of musclespecific genes [10]. Each MRF can initiate myogenesis in a variety of non-myogenic cells [11–13], but this myogenic conversion requires the function of the MEF2 family [14,15]. However, MEF2 proteins are not sufficient to induce myogenesis [9,15,16]. Each of the MRFs has been shown to heterodimerize with the ubiquitous bHLH E proteins, including E12 and E47 (generated by alternative splicing of E2A), ITF-2, and HEB [13,17,18]. The MRF/E protein heterodimers bind to DNA at E-boxes (CANNTG) that are present in the promoters of many skeletal muscle-specific genes such as desmin, creatine kinase, troponin I, alpha-actin, and acetylcholine receptor subunits [19–21]. MRF/E protein heterodimers interact with MEF2 proteins to cooperatively and synergistically activate myogenesis [16,22]. Activation of the Notch pathway inhibits myogenic differentiation [23,24]. The differentiation of the murine myogenic C2C12 cell line is markedly inhibited by the ectopic expression of NICD [5,25], but not by expression of full-length Notch [25]. Similar results have been reported in MyoD- or Myf5-converted fibroblasts in which NICD has been overexpressed [25]. The co-culture of C2C12 cells with cells expressing one of the Notch ligands also inhibits differentiation [26,27]. Notch-mediated inhibition of myogenesis is accompanied by a down-regulation of myogenin and myosin light chain 2 [23,26–28]. Removal of the two nuclear localization signals present in NICD inhibits its nuclear translocation and abolishes the ability of NICD to inhibit differentiation [25], presumably due to the failure to activate CSL-dependent gene expression, including the induction of Hes gene expres-

614

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

sion. Hes1 transcription is rapidly induced by Notch activation in C2C12 cells, and this induction is correlated with an inhibition of differentiation [26,29]. The overexpression of Hes1 blocks myogenesis induced by MyoD in 10T1/2 cells [30]. However, Hes1 overexpression alone does not block C2C12 differentiation, suggesting that other factors, including perhaps other Hes genes, are involved in the regulating myogenesis in these cells [23]. The mechanisms by which Hes genes inhibit myogenesis appear to be multifactorial. Among the Hes genes, both Hes1 and Hes2 can suppress MyoD activity by inhibiting the activity of E47 [30,31]. In addition, RBP-J-dependent activation of Hes1 in response to Notch signaling leads to an inhibition of MyoD expression [29]. Likewise, overexpression of a constitutively active form of RBP-J inhibits muscle differentiation by blocking the expression of MyoD [5,29]. The regulation of myogenesis by Hes gene expression, however, is not unidimensional. Overexpression of Hes6 impairs C2C12 cell differentiation, blocking the induction of the cyclin-dependent kinase inhibitor, p21Cip1 , and thus maintaining cells in the cell cycle and preventing their withdrawal to undergo irreversible cell cycle arrest [32]. However, Hes6 may also have pro-myogenic actions. First, the expression of Hes6 increases during C2C12 differentiation [32]. Second, Hes6 has been shown to bind and inhibit transcription repression of Hes1 and induce neuronal differentiation [33,34]. Hes6 could also promote myogenic differentiation by a similar mechanism. Hes6 doesn’t bind DNA itself but suppresses both binding of Hes1 to E box sequences and Hes1 transcriptional repression, and inhibits Hes1/E47 heterodimer formation [34]. Hes6 may also promote myogenesis by suppressing the expression of MyoR (or “musculin”), an antagonist of MyoD that acts by blocking the activation of E-box dependent muscle genes [35]. Finally, a dominant negative mutant of Hes6 blocks myogenic differentiation, partly due to de-repression of the expression of MyoR [36]. In addition to the canonical CSL-dependent pathway involving downstream Hes and Hey genes, activated Notch can also inhibit myogenesis by a less well characterized CSLindependent pathway [23]. Weinmaster and co-workers have demonstrated that truncated forms of NICD which can not bind to CBF1 and activate transcription can still prevent C2C12 differentiation, and that myogenic differentiation is not inhibited by the expression of a dominant negative form of CBF1 [23,24]. This CBF1-independent pathway may be related to the ability of NICD to inhibit E47, and thus MyoD, activity [31]. NICD does not appear to act by any direct effect on the ability of MyoD to bind DNA, to heterodimerize with E proteins, or to activate transcription [25]. Activated forms of Notch do inhibit the DNA binding of MEF2C and its cooperative activity with MyoD and myogenin to activate myogenesis [13]. This interaction is dependent upon a 12 amino acid region which is unique to the MEF2C isoform, accounting for the specificity of interactions with this one member of the MEF2 family [13]. Therefore, although there are data showing that downstream effectors of the Notch

signaling pathway (e.g. Hes6) can promote myogenesis, the bulk of evidence indicates that activation of Notch signaling inhibits myogenic differentiation, and this inhibition occurs by several distinct mechanisms.

3. Notch signaling in satellite cell activation and postnatal myogenesis Notch signaling during development of skeletal muscle is complex, being involved in pattern formation and cyclic gene expressing during somitogenesis [37–39]. Following embryonic development and postnatal growth, skeletal muscle is composed predominantly of postmitotic, multinucleated myofibers that are responsible for the ability of muscle to contract, generate force, and produce movement. There is also a population of mononucleated muscle stem cells, or “satellite cells”, that reside in mature muscle [40]. Satellite cells activate in response to both physiological stimuli (e.g. exercise) and pathological conditions (e.g. injury, degenerative diseases) to generate a committed population of myoblasts that are capable of fusion and differentiation. Myoblasts fuse with each other to form multinucleated myotubes during muscle regeneration, or they fuse with existing myofibers to mediate muscle repair or hypertrophy [41,42]. Nuclei of satellite cells account for less than 2–3% of the nuclei of adult mouse skeletal muscle and yet are capable of generating a sufficient number of myoblasts to regenerate an entire muscle, probably multiple times over [43]. The molecular mechanisms controlling postnatal myogenesis, characterized by satellite cell activation, the proliferative activity of satellite cell progeny, cell fate decisions of those progeny, and the differentiation of myoblasts, are complex and involve multiple signaling pathways [41,42]. The Notch signaling pathway is critical to multiple stages of satellite cell activation and postnatal myogenesis. Within 24 h after a muscle injury, there is an increase in expression of the Notch ligand, Delta [44]. Interestingly, Delta appears to be expressed both in activated satellite cells and in uninjured myofibers adjacent to the site of injury. The increase of Delta levels is paralleled by the appearance of the activated form of Notch. During this early phase, Notch activation strongly promotes the proliferation of satellite cell progeny and a rapid expansion of a pre-myoblast population, termed “intermediate progenitor cells”. These cells have a remarkable proliferative potential with a very rapid cell cycle time, and generate a large number of progenitor cells. Inhibition of Notch signaling during this early phase of satellite cell activation prevents the expansion of the intermediate progenitor population and thus inhibits effective muscle regeneration. Following the expansion of this early progenitor population, a decline in Notch signaling is necessary for intermediate progenitor cells to progress to becoming fusion competent myoblasts [44]. This regulation is likely mediated at least in part by the increased expression of the Notch inhibitor,

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

Numb. Interestingly, Numb is expressed in subsets of cells and its presence promotes the progression of cells down the myogenic lineage pathway, whereas the absence of Numb maintains cells in the intermediate progenitor stage [44]. Little is known about the regulation of Numb at the transcriptional or post-transcriptional levels or whether other regulatory processes are involved in the downregulation of Notch signaling at this stage. Musashi is an RNA-binding protein which induce a decrease of Numb expression at translational level [45,46]. Based on the ability of satellite cells to participate in repeated rounds of regeneration without a depletion of the satellite cell number, it has been proposed satellite cells are capable of self-renewal, as would be expected of bona fide tissue-specific stem cells. Recent in vitro studies of satellite cells still associated with myofibers provide direct evidence of multiple cell fates among satellite cell progeny, with preliminary evidence that one of those fates is to return toward the phenotype of the quiescent satellite cell [47]. Currently, there is no evidence as to a molecular mechanism of satellite cell self-renewal. However, it is intriguing that at the time that Numb levels are beginning to increase during satellite cell activation, Numb becomes localized asymmetrically in a subset of the cells [44]. As this asymmetry occurs in dividing cells and the segregation is perpendicular the plane of cell division, this strongly suggests that Numb participates in an asymmetric cell division, exactly as occurs during Drosophila development in many tissues [48]. Such asymmetric cell divisions are commonly associated with processes of stem cell self-renewal, and such could be the case for activated satellite cells. Although mechanisms of asymmetric Numb localization have been described in Drosophila, comparable

615

mechanisms have not been elucidated in mammalian muscle progenitor cells. Finally, a further inhibition of Notch signaling is necessary for differentiation and fusion of myoblasts to become myotubes [44], consistent with the data from C2C12 cells described above. The requisite decline in Notch signaling may also be regulated by Numb, which is highly expressed at this phase. However, the details of which of the four Numb isoforms (see below) are expressed in satellite cell progeny and whether they differ in terms of regulation Notch signaling remains to be determined. Furthermore, other regulatory mechanisms that may be critical to inhibiting Notch signaling for effective differentiation and muscle regeneration have not been explored. It is clear that Notch signaling needs to be tightly regulated both spatially and temporally for effective postnatal myogenesis and that small changes, either positively or negatively, can profoundly alter the normal regenerative processes. Thus, as is the case during embryogenesis, the Notch ligand-receptor signaling pathway is very susceptible to small changes in “dosage” since this is fundamentally a non-amplifying signaling pathway. While key regulatory processes related to ligand and inhibitor expression have been elucidated during satellite cell activation, multiple levels of regulation of Notch signaling are likely to contribute to normal satellite cell activation, cell fate decisions of satellite cell progeny, and control of proliferation and differentiation of progenitor cells along the myogenic lineage pathway. In the following section, we review several of the key regulatory pathways that modulate Notch signaling in various tissues and that may play a role in regulating Notch signaling during satellite cell activation and postnatal myogenesis. Table 1

Fig. 1. Diagrammatic representation of regulatory proteins and processes for the Notch signaling pathway.

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

Dsh-1 Dsh-2 Mig-5 Sel-10

Sel-10 FBW7/FBXW7/ CDC4/AGO

Dishevelled

Dishevelled

616

Suppressor of Deltex (Su(dx)) Hairy and Enhancer of Split (E(spl))

Numb

Deltex

4.1.1. Background, structure Numb was first identified as a gene controlling cell fate specification in development of the Drosophila peripheral nervous system [49]. Numb is an adapter protein that contains an N-terminal phosphotyrosine binding (PTB) domain and a C-terminal proline-rich region (PRR) [50]. There are four mammalian isoforms of Numb which differ by the presence or absence of an 11 amino acid insertion in PTB domain and the presence or absence of a 49 amino acid insertion in the PRR domain [51,52]. The PRR domain contains several putative SH3 domain-binding sites and an Esp15 homology domain-binding motif [53]. Numb binds via its PTB domain to two regions of Notch, the RAM domain and the C-terminal domain [54]. In mammals, a homolog of Numb, Numblike, has been described [55]. Numb isoforms with the PTB insertion localize to the plasma membrane, perhaps by more efficient binding to phospholipids [51], whereas those without the PTB domain insertion do not. In Drosophila neuroblasts, Numb is recruited to plasma membrane by Numb-interacting proteins [56]. As described below, Numb appears to regulate Notch signaling by ubiquitin-mediated protein degradation, but Numb itself appears to be regulated by the activities of various E3 ubiquitin ligases such as LNX, Siah1, and mdm2 [57–61]. Lag-1 Lag-2 APX-1 Lin-12 GLP-1 C. elegans

Serrate1 Serrate2

Delta Notch D. melanogaster

Delta-like3 Delta-like4 Jagged1 Notch3 Notch4

Jagged2

Delta-like1 Delta-like2 Notch1 Notch2 Mammals

4. Regulators of Notch signaling: potential mechanisms of regulation of postnatal myogenesis 4.1. Numb

Suppressor of Hairless (Su(H))

Numb-p71 Numb-p72 Numb-like HES6 HES7 Enhancer-of-split related 1 (ESR1)

Deltex3 Deltex4

Itch Deltex1 Deltex2 Numb-p65 Numb-p66 HES1 HES5 CBF1/RBP-J␬/KBF2

Other Notch interacting proteins CSL-dependent Notch target genes Transcription factors (CSL family members) Ligands (DSL family members) Receptors

Table 1 Major components of the Notch signaling pathway and Notch binding proteins in different species

presents a list of components of the Notch signaling pathway as reported in different species. Fig. 1 is a diagrammatic representation of cellular localization of various components of the Notch pathway, their protein-protein interactions, and their involvement in various cellular processes that lead to an activation or inhibition of Notch signaling.

4.1.2. Cellular functions The expression of Numb clearly regulates the progression of satellite cell progeny along the myogenic lineage pathway [44], promoting commitment and differentiation by inhibiting Notch signaling as described above. However, the effects of Numb on cellular differentiation may depend upon the specific isoforms expressed. Numb isoforms with the PRR insert decrease during retinoic acid induced differentiation of P19 cells [51]. By contrast, ectopic expression of Numb isoforms without the PRR insertion increased the differentiation of PC12 cells treated with nerve growth factor [62]. As described above, Numb is important in asymmetric cell division and cell fate determination in satellite cell progeny [44], a functionality that has been described in detail during Drosophila development. Numb is involved during the process of the asymmetric division that results in daughter cells adopting divergent fates in Drosophila and mouse neurogenesis [63,64]. Numb protein is asymmetrically localized in

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

both neuroblasts and sensory organ precursor cells [65–68]. Following cell division, one daughter cell inherits Numb and that cell becomes post-mitotic and differentiates into a neuron or glial cell. The other daughter cell, which doesn’t inherit Numb, remains a progenitor cell [63,69]. In certain cases, asymmetric inheritance of Numb leads to two daughters cells both of which are neurons but differ phenotypically [64,69]. 4.1.3. Molecular mechanisms The cellular effects of Numb expression and/or segregation are presumed to be due to the ability of Numb isoforms to inhibit Notch signaling. Below, we focus on studies of two specific cellular processes—endocytosis and ubiquitinmediated protein degradation—that may shed new light on the molecular mechanisms of the inhibition of Notch signaling by Numb. 4.1.3.1. Endocytosis. Signaling by transmembrane receptors is often regulated by receptor endocytosis, thus altering the number of receptors on the cell surface. Receptors are rapidly internalized by endocytosis into intracellular vesicles and targeted for degradation. There is considerable evidence that endocytosis of both Notch and its ligands is an important process for the regulation of Notch signaling during development [70]. Evidence that Numb may inhibit Notch signaling by inducing the internalization of Notch is exemplified by the finding that the expression of a dominant negative mutant of Numb disrupts endocytosis of cell surface receptors such as the EGF receptor and the transferrin receptor [71]. In Drosophila and mammals, Numb has been found to bind a family of endocytic proteins, EHD/Rme-1/Pincher [72]. The function of these proteins is to recycle plasma membrane receptors either by clathrin-mediated endocytosis or by a clathrin-independent pathway that is regulated by ARF ribosylation factor 6 (Arf6) [72,73]. Numb co-localizes with both EDH4/Pincher and Arf6 [72]. Numb also interacts with Esp15, a component of the endocytic machinery [53], and with ␣-adaptin, a clathrin coat component and a subunit of the AP-2 complex [71,74]. Numb localizes to endocytic vesicles and co-traffics with internalizing cell surface receptors [71]. Numb have been proposed to be an adaptor between ␣adaptin and internalized Notch receptor [74]. In Drosophila, an alternative pathway has been described that involves Sanpodo, a predicted transmembrane protein which is asymmetrically localized during the central neural system development [75]. Sanpodo positively regulates Notch signaling at the plasma membrane and Numb inhibits the Notch pathway by inducing Sanpodo endocytosis [75–77]. 4.1.3.2. Ubiquitin-mediated protein degradation. Some studies have suggested a role for the ubiquitin/proteasome degradation pathway in controlling Notch signaling [78]. In the presence of a proteasome inhibitor, the amount of NICD protein and the level of its ubiquitination are increased [79,80]. The accumulation of ubiquitinated NICD decreases

617

the activation of the Hes1 promoter. The ubiquitinated NICD seems to be less potent transactivator [79]. The ubiquitination pathway regulates protein fate by a small polypeptide (76 aa) which covalently binds to proteins in a multi-steps reaction. The process is initiated by the attachment of ubiquitin to an ubiquitin-activating enzyme (E1), and its transfer to an ubiquitin-conjugating enzyme (E2). E3 ubiquitin ligase, in association with E2, specifically transfers ubiquitin to the protein substrate [81]. In addition to targeting a protein for proteasome degradation, ubiquitin can be used as a signal for receptor internalization by the endocytic pathway and subsequent degradation by the lysosome [81–83]. In mammalian cells, Numb induces ubiquitination of Notch, and this ubiquitination is associated with a loss of transcriptional activation of the Hes1 promoter [84]. Only isoforms with the PTB domain insertion are capable of ubiquitinating and down-regulating Notch. This ubiquitination occurs only on NICD and not on the full length Notch receptor [84]. 4.2. Deltex 4.2.1. Background, structure The Deltex gene was first isolated in a genetic screen in Drosophila aimed at identifying suppressors of Notch mutations [85]. Mutation in the Deltex locus suppresses Notch mutants. Subsequent studies indicated that dDeltex is a cytoplasmic protein that is co-localized with Notch in vivo [86,87]. Further molecular and genetic analysis showed that dDeltex binds to Notch cytoplasmic ankyrin repeats domain and acts as a positive regulator of Notch signaling pathway [88]. Only one isoform of Deltex gene has been found in Drosophila, but a Deltex gene family has been found in both human [89,90] and mouse [91]. The members are designated Deltex1, Deltex2A, Deltex2B and Deltex3. A predicted Deltex4 gene sequence has also been reported (Gene bank accession number: XM 166213, NM 172442). The mammalian Deltex1 is the homologue most closely related to the Drosophila Deltex [89]. The N-terminal portion of the Deltex protein contains domain I that is necessary and sufficient to bind the ankyrin repeats of Notch [88]. Deltex3 lacks most of domain I and does not bind to Notch [91]. The most conserved region is domain III that is within the carboxy-terminal part of the protein and includes the RING-H2 finger motif that is found in one class of E3-ubiquitin ligases [92], and is involved in protein–protein interactions in various systems [93,94]. dDeltex forms homo-multimers, and mutations in the RING-H2 finger domain abolishes this oligomerization [88]. Deltex3 has a different RING finger motif (C3HC4) compared with the other Deltex proteins, although the rest of Deltex3 domain III is similar. In an in vitro ubiquitination assay, hDeltex1, hDeltex2A, hDeltex2B, and hDeltex3 all exhibited E3 ligase activity as assessed by self-ubiquitination [90]. Domain II has a proline-rich region similar to the consensus sequence of SH-3 domain binding sites [88,90,91]. Deltex2B

618

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

lacks this proline-rich motif. A mutant form of dDeltex that lacks the proline-rich motif behaves as a dominant-negative [95]. It remains to be explored whether mammalian Deltex2B acts as a dominant-negative or antagonist of Deltex2A. There is a WWE domain in the N-terminal region of Deltex, and this domain has a predicted function as a common interaction module in protein ubiquitination and ADP ribosylation [96]. 4.2.2. Cellular functions In general, Deltex appears to be a positive regulator of Notch signaling, with notable exceptions. Overexpression of Deltex2 has been shown to inhibit myogenesis, comparable to the effects of Notch activation and consistent with the idea that Deltex is a positive regulator of Notch signaling [91]. Kishi et al. showed that overexpression of mouse Deltex2 in C2C12 cells under differentiation-inducing conditions suppressed the expression of myogenin [91]. We have found that the constitutive expression of mouse Deltex1 and Deltex2 inhibits C2C12 cell differentiation [97]. Deltex1 plays a regulatory role in neurogenesis [91], B cell development [98,99], and oligodendrocyte maturation and myelination [100,101]. During neurogenesis, Deltex mediates a Notch signal to block differentiation of neural progenitor cells [102]. During lymphocyte development Notch1 signaling drives T cell development at the expense of B cell development from a common precursor. However, forced expression of Deltex1 in hematopoietic progenitors results in B cell development at the expense of T cell development in fetal thymic organ culture and in vivo [98], suggesting that Deltex1 antagonizes Notch1 signaling in common lymphocyte precursors to promote a B cell fate. However, normal immune system development has been reported in mice lacking the Deltex1 RING finger domain, suggesting that the Deltex1 ubiquitin ligase activity is dispensable for mouse development and immune function [103]. 4.2.3. Molecular mechanisms Genetic screens in Drosophila showed that mutations in the Deltex locus suppress Notch mutants, indicating Deltex plays an important role in the Notch signaling pathway [85,104]. Most Deltex mutant alleles yield a recessive wingnotch phenotype similar to that of Notch mutants. Overexpression of Deltex induces an ectopic wing margin-like structure, which is similar to the consequence of the ectopic expression of activated forms of Notch, though with distinct inductive properties in the wing pouch [95]. These data suggest that phenotypes caused by Deltex loss-of-function or gain-of-function mutations are similar to those caused by the same types of Notch mutations. In early studies of the biochemical basis of Deltex actions, it was found that dDeltex was a positive regulator of Notch signaling by its effects on Su(H) localization [88]. In the absence of Notch signaling, it appeared that Su(H) was sequestered in the cytoplasm by binding to the Notch ankyrin repeats. Therefore, in this model, when the ligand Delta binds to Notch, Deltex then binds to the cytoplasmic domain of

Notch, releasing Su(H) and promoting its translocation to the nucleus where it functions as a transcription factor for the E(spl) complex. In turn, E(spl) suppresses neural development [105]. This model suggests that Deltex acts in a CSL-dependent manner. However, this model is inconsistent with subsequent observations that NICD translocates to the nucleus following ligand binding to Notch, that CSL proteins appear to be localized to the nucleus even in the absence of Notch signaling, and that the interaction of NICD with CSL proteins convert them from default repressors into transcriptional activators [1,4–6]. Therefore, the mechanism by which Deltex acts as a positive regulator of Notch signaling in a CSL-dependent manner needs to be reconsidered in light of these findings. In addition, several lines of evidence indicate that Deltex can mediate some of the CSL-independent Notch signaling events [31,101,106–108]. In a genetic analysis of a new class of Notch alleles, NotchMcd , carried out in Drosophila, it was shown that the phenotype of these mutants is not the consequence of increased signaling through the Su(H)-dependent pathway but rather through a pathway that requires Deltex function [107]. Further evidence has been found that Deltex-dependent activation of the Notch signaling pathway which is independent of Su(H) occurs in the late-endosomal compartments [108]. In vertebrates, it is not known whether Deltex may play a role in the CSL-independent pathway by which Notch signaling may inhibit myogenic differentiation [23,24]. Several studies have addressed the potential molecular mechanisms by which Deltex mediates CSL-independent Notch signaling pathway. First, Deltex1 may act as a transcriptional regulator. Through its binding to p300, Deltex1 inhibited transcriptional activation by the neural-specific bHLH transcription factor MASH1, and this mechanism may account for the inhibition of neural progenitor cell differentiation by Deltex [102]. Second, the human Deltex proteins (Deltex1, 2, 3) function as E3 ligases based on their capacity for self-ubiquitination [90]. The C-terminal catalytic fragment of MEKK1, the dominant active form of MEKK1, is a target of Deltex E3 ubiquitin ligase in T cells [109]. Third, Notch and Deltex may act on E47 by inhibiting signaling through Ras [31]. Clearly, this interaction could be important the regulation of myogenesis by Deltex. Fourth, although Deltex is commonly recognized as a cytoplasmic protein, Deltex1 and 2 have been detected in the nucleus in the neuroepithelial MNS-7 cell line [102]. Furthermore, we have found that exogenous mDeltex2 can be detected only in the nucleus in C2C12 cells whereas mDeltex1 is detected in the cytoplasm [97], suggesting that Deltex2 may function by different mechanisms than Deltex1. 4.3. ITCH, Su(dx) Suppressor of Deltex (Su(dx)) was identified genetically as a dominant suppressor of Deltex and is a negative regulator of Notch signaling [110,111]. The overexpression of

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

Su(dx) blocks both the endogenous activity of Notch and the enhancement of Notch signaling induced by overexpression of Deltex [112]. Su(dx) is an E3 ubiquitin ligase and a member of Nedd4/RSP5 family of HECT domain proteins. These proteins are characterized by an N-terminal membrane binding C2 domain, 2 to 4 WW domains and a C-term HECT domain which contains the E3 ubiquitin ligase activity [111]. Itch, the mouse homolog of Su(dx), has been shown to bind Notch via its WW domains [77,113]. Itch has also been shown to ubiquitinate Notch [114]. Members of the Nedd4 family of proteins are involved in ubiquitination, internalization and lysosomal degradation of membrane channels and permease proteins [115]. Therefore Itch, like Numb, may act as a negative regulator of Notch signaling by promoting both endocytosis and degradation. Intriguingly, it appears that Numb can interact with Itch in C2C12 cells to cooperatively promote ubiquitination of Notch [84]. 4.4. Sel-10 Sel-10 was identified in Caenorhabditis elegans as a negative regulator of Lin-12, which encodes a Notch-like receptor [116,117]. Sel-10 is a member of the cdc4 family of F-box/WD40 repeat-containing proteins, and is a component of the SCF (Skp1–Cullin–F-box) class of E3 ubiquitin ligases [117]. The Sel-10 protein can interact with the intracellular domain of Notch receptors in both C. elegans and mammalian cells [117]. Similarly, mammalian Sel-10 homologues (Fbxw7, hSel-10) can interact with NICD [118] via their WD repeats [79,80,119]. Intriguingly, mammalian Sel-10 appears to interact specifically with nuclear forms of NICD where a phosphorylation of NICD occurs that is required for Sel-10 binding [80,118]. Like Numb, Sel-10 both appears to regulate Notch by ubiquitination (see below) and is itself ubiquitinated and degraded by the proteasome [79]. 4.4.1. Ubiquitination and proteasome degradation Fbxw7, a mouse Sel-10 homologue, binds nuclear NICD and decrease its activation of Hes1 [79]. Sel-10 is involved in the negative regulation of Notch signaling by inducing NICD degradation. Sel-10 and homologues, in association with SCF components [80], mediate NICD ubiquitination and degradation by the proteasome [79,80,118,120]. SCF ligases containing recombinant Sel-10 are capable of ubiquitinating Notch in vitro [80,118]. A dominant negative of mammalian Sel-10 stabilizes the nuclear form of NICD and increase the transcriptional activity of Notch1 [118] but not Notch4 [80]. The absence of Fbxw7 leads to an increase of the abundance of NICD by limiting degradation and stimulates the downstream transcriptional pathways involving Hes1, Hey1, Herp1, and Herp2 [120,121]. Sel-10 and mammalian homologues can also regulate the Lin-12/Notch signaling pathway by inducing the ubiquitin-mediated proteasomal degradation of SEL-12/PS1 presenilins [80,119, 122,123].

619

4.5. Dishevelled Dishevelled is a cytoplasmic protein involved in the Wnt signaling pathway [124]. Dishevelled also acts in a distinct pathway that activates jun N-terminal kinase (JNK) [125]. Notch signaling is inhibited by the binding of Dishevelled to NICD [126]. The NotchMcd alleles, which result in a phenotype that is opposite to the Notch or Su(H) loss of function phenotype that is Su(H)-independent but Deltexdependent, encode carboxy-terminally truncated receptors [107]. These truncations eliminate the region of the receptor that binds to Dishevelled, suggesting that NotchMcd proteins escape inhibition by Dishevelled [107]. These data suggest that Notch signaling can act as a CSL-independent, Deltex-dependent, but Dishevelled-regulated manner. Previous studies had shown that two regions in the Notch protein are involved in the CSL-independent modulation of JNK signaling activity in the dorsal-most cells of the epidermis through regulation of actin dynamics [127]. The Cdc10/ankyrin repeat region, which is the Deltex binding domain, mediates the down-regulation of the JNK pathway, and the Dishevelled binding region regulates this inhibitory function [127]. Whether Deltex protein is involved in this regulation remains to be investigated. 5. Summary Clearly, the regulation of Notch signaling involves numerous cellular processes and a multiplicity of regulatory proteins. Many of these regulatory proteins are likely to contribute to the dynamics of Notch signaling during satellite cell activation and myogenic lineage progression. Beyond the proteins and associated processes considered in this review, there are additional levels of regulation, including post-translational modification of the Notch receptors and modulation of the proteolytic cleavage processes that may turn out to be important in postnatal myogenesis. Furthermore, direct interactions between other pathways that have been implicated in satellite cell activation, such as those mediated by hepatocyte growth factor and its receptor (c-met) [128], FGF ligands and their receptors [129], and the Wnt signaling pathway [130], are certain to add complexity to the regulation of myogenesis by Notch signaling. Acknowledgements This preparation of this review was supported by grants from the NIH (AG23806), the Department of Veterans Affairs, and the Ellison Medical Foundation to T.A.R. References [1] Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999;284:770–6.

620

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

[2] Greenwald I. LIN-12/Notch signaling: lessons from worms and flies. Genes Dev 1998;12:1751–62. [3] Mumm JS, Kopan R. Notch signaling: from the outside in. Dev Biol 2000;228:151–65. [4] Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch. Nature 1995;377:355–8. [5] Kato H, Taniguchi Y, Kurooka H, Minoguchi S, Sakai T, NomuraOkazaki S, et al. Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development 1997;124:4133–41. [6] Egan SE, St-Pierre B, Leow CC. Notch receptors, partners and regulators: from conserved domains to powerful functions. Curr Top Microbiol Immunol 1998;228:273–324. [7] Molkentin JD, Olson EN. Combinatorial control of muscle development by basic helix-loop-helix and MADS-box transcription factors. Proc Natl Acad Sci USA 1996;93:9366–73. [8] Yun K, Wold B. Skeletal muscle determination and differentiation: story of a core regulatory network and its context. Curr Opin Cell Biol 1996;8:877–89. [9] Black BL, Molkentin JD, Olson EN. Multiple roles for the MyoD basic region in transmission of transcriptional activation signals and interaction with MEF2. Mol Cell Biol 1998;18:69–77. [10] Fickett JW. Coordinate positioning of MEF2 and myogenin binding sites. Gene 1996;172:19–32. [11] Olson EN. MyoD family: a paradigm for development? Genes Dev 1990;4:1454–61. [12] Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987;51:987–1000. [13] Wilson-Rawls J, Molkentin JD, Black BL, Olson EN. Activated Notch inhibits myogenic activity of the MADS-Box transcription factor myocyte enhancer factor 2C. Mol Cell Biol 1999;19:2853–62. [14] Black BL, Olson EN. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol 1998;14:167–96. [15] Ornatsky OI, Andreucci JJ, McDermott JC. A dominant-negative form of transcription factor MEF2 inhibits myogenesis. J Biol Chem 1997;272:33271–8. [16] Molkentin JD, Black BL, Martin JF, Olson EN. Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell 1995;83:1125–36. [17] Petropoulos H, Skerjanc IS. Analysis of the inhibition of MyoD activity by ITF-2B and full-length E12/E47. J Biol Chem 2000;275:25095–101. [18] Hu JS, Olson EN, Kingston RE. HEB, a helix-loop-helix protein related to E2A and ITF2 that can modulate the DNA-binding ability of myogenic regulatory factors. Mol Cell Biol 1992;12:1031–42. [19] Lassar A, Munsterberg A. Wiring diagrams: regulatory circuits and the control of skeletal myogenesis. Curr Opin Cell Biol 1994;6:432–42. [20] Olson EN, Klein WH. bHLH factors in muscle development: dead lines and commitments, what to leave in and what to leave out. Genes Dev 1994;8:1–8. [21] Weintraub H. The MyoD family and myogenesis: redundancy, networks, and thresholds. Cell 1993;75:1241–4. [22] Kaushal S, Schneider JW, Nadal-Ginard B, Mahdavi V. Activation of the myogenic lineage by MEF2A, a factor that induces and cooperates with MyoD. Science 1994;266:1236–40. [23] Shawber C, Nofziger D, Hsieh JJ, Lindsell C, Bogler O, Hayward D, et al. Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway. Development 1996;122:3765–73. [24] Nofziger D, Miyamoto A, Lyons KM, Weinmaster G. Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts. Development 1999;126:1689–702. [25] Kopan R, Nye JS, Weintraub H. The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis

[26]

[27] [28]

[29]

[30]

[31]

[32] [33]

[34]

[35]

[36]

[37]

[38]

[39] [40] [41] [42] [43]

[44]

[45]

[46] [47]

directed at the basic helix-loop-helix region of MyoD. Development 1994;120:2385–96. Jarriault S, Le Bail O, Hirsinger E, Pourquie O, Logeat F, Strong CF, et al. Delta-1 activation of Notch-1 signaling results in HES-1 transactivation. Mol Cell Biol 1998;18:7423–31. Lindsell CE, Shawber CJ, Boulter J, Weinmaster G. Jagged: a mammalian ligand that activates Notch1. Cell 1995;80:909–17. Hsieh JJ, Nofziger DE, Weinmaster G, Hayward SD. Epstein-Barr virus immortalization: Notch2 interacts with CBF1 and blocks differentiation. J Virol 1997;71:1938–45. Kuroda K, Tani S, Tamura K, Minoguchi S, Kurooka H, Honjo T. Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis. J Biol Chem 1999;274:7238–44. Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S. Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev 1992;6:2620–34. Ordentlich P, Lin A, Shen CP, Blaumueller C, Matsuno K, Artavanis-Tsakonas S, et al. Notch inhibition of E47 supports the existence of a novel signaling pathway. Mol Cell Biol 1998;18:2230–9. Cossins J, Vernon AE, Zhang Y, Philpott A, Jones PH. Hes6 regulates myogenic differentiation. Development 2002;129:2195–207. Gratton MO, Torban E, Jasmin SB, Theriault FM, German MS, Stifani S. Hes6 promotes cortical neurogenesis and inhibits Hes1 transcription repression activity by multiple mechanisms. Mol Cell Biol 2003;23:6922–35. Bae S, Bessho Y, Hojo M, Kageyama R. The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation. Development 2000;127:2933–43. Lu J, Webb R, Richardson JA, Olson EN. MyoR: a musclerestricted basic helix-loop-helix transcription factor that antagonizes the actions of MyoD. Proc Natl Acad Sci USA 1999;96:552–7. Gao X, Chandra T, Gratton MO, Quelo I, Prud’homme J, Stifani S, et al. HES6 acts as a transcriptional repressor in myoblasts and can induce the myogenic differentiation program. J Cell Biol 2001;154:1161–71. Conlon RA, Reaume AG, Rossant J. Notch1 is required for the coordinate segmentation of somites. Development 1995;121:1533–45. Hrabe de Angelis M, McIntyre J, Gossler A. Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 1997;386:717–21. Pourquie O. Notch around the clock. Curr Opin Genet Dev 1999;9:559–65. Mauro A. Satellite cells of skeletal muscle fibers. J Biophys Biochem Cytol 1961;9:493–5. Hawke TJ, Garry DJ. Myogenic satellite cells: physiology to molecular biology. J Appl Physiol 2001;91:534–51. Charg´e SB, Rudnicki MA. Cellular and molecular regulation of muscle regeneration. Physiol Rev 2004;84:209–38. Zammit PS, Heslop L, Hudon V, Rosenblatt JD, Tajbakhsh S, Buckingham ME, et al. Kinetics of myoblast proliferation show that resident satellite cells are competent to fully regenerate skeletal muscle fibers. Exp Cell Res 2002;281:39–49. Conboy IM, Rando TA. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev Cell 2002;3:397–409. Imai T, Tokunaga A, Yoshida T, Hashimoto M, Mikoshiba K, Weinmaster G, et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol Cell Biol 2001;21:3888–900. Okano H, Imai T, Okabe M. Musashi: a translational regulator of cell fate. J Cell Sci 2002;115:1355–9. Zammit PS, Golding JP, Nagata Y, Hudon V, Partridge TA, Beauchamp JR. Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J Cell Biol 2004;166:347–57.

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622 [48] Roegiers F, Jan YN. Asymmetric cell division. Curr Opin Cell Biol 2004;16:195–205. [49] Uemura T, Shepherd S, Ackerman L, Jan LY, Jan YN. Numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos. Cell 1989;58:349–60. [50] Verdi JM, Schmandt R, Bashirullah A, Jacob S, Salvino R, Craig CG, et al. Mammalian NUMB is an evolutionarily conserved signaling adapter protein that specifies cell fate. Curr Biol 1996;6:1134–45. [51] Dho SE, French MB, Woods SA, McGlade CJ. Characterization of four mammalian numb protein isoforms. Identification of cytoplasmic and membrane-associated variants of the phosphotyrosine binding domain. J Biol Chem 1999;274:33097–104. [52] Verdi JM, Bashirullah A, Goldhawk DE, Kubu CJ, Jamali M, Meakin SO, et al. Distinct human NUMB isoforms regulate differentiation vs. proliferation in the neuronal lineage. Proc Natl Acad Sci USA 1999;96:10472–6. [53] Salcini AE, Confalonieri S, Doria M, Santolini E, Tassi E, Minenkova O, et al. Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module. Genes Dev 1997;11:2239–49. [54] Guo M, Jan LY, Jan YN. Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Neuron 1996;17:27–41. [55] Zhong W, Jiang MM, Weinmaster G, Jan LY, Jan YN. Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. Development 1997;124:1887–97. [56] Qin H, Percival-Smith A, Li C, Jia CY, Gloor G, Li SS. A novel transmembrane protein recruits numb to the plasma membrane during asymmetric cell division. J Biol Chem 2004;279:11304–12. [57] Dho SE, Jacob S, Wolting CD, French MB, Rohrschneider LR, McGlade CJ. The mammalian Numb phosphotyrosine-binding domain. Characterization of binding specificity and identification of a novel PDZ domain-containing numb binding protein, LNX. J Biol Chem 1998;273:9179–87. [58] Nie J, McGill MA, Dermer M, Dho SE, Wolting CD, McGlade CJ. LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation. Embo J 2002;21:93–102. [59] Susini L, Passer BJ, Amzallag-Elbaz N, Juven-Gershon T, Prieur S, Privat N, et al. Siah-1 binds and regulates the function of Numb. Proc Natl Acad Sci USA 2001;98:15067–72. [60] Yogosawa S, Miyauchi Y, Honda R, Tanaka H, Yasuda H. Mammalian Numb is a target protein of Mdm2, ubiquitin ligase. Biochem Biophys Res Commun 2003;302:869–72. [61] Juven-Gershon T, Shifman O, Unger T, Elkeles A, Haupt Y, Oren M. The Mdm2 oncoprotein interacts with the cell fate regulator Numb. Mol Cell Biol 1998;18:3974–82. [62] Pedersen WA, Chan SL, Zhu H, Abdur-Rahman LA, Verdi JM, Mattson MP. Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 Cells. J Neurochem 2002;82:976–86. [63] Shen Q, Zhong W, Jan YN, Temple S. Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 2002;129:4843–53. [64] Cayouette M, Raff M. Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals. Nat Neurosci 2002;5:1265–9. [65] Rhyu MS, Jan LY, Jan YN. Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells. Cell 1994;76:477–91. [66] Knoblich JA, Jan LY, Jan YN. Asymmetric segregation of Numb and Prospero during cell division. Nature 1995;377:624–7. [67] Spana EP, Kopczynski C, Goodman CS, Doe CQ. Asymmetric localization of Numb autonomously determines sibling neu-

[68]

[69] [70]

[71]

[72]

[73] [74]

[75]

[76]

[77] [78] [79]

[80]

[81] [82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

621

ron identity in the Drosophila CNS. Development 1995;121:3489– 94. Vervoort M, Merritt DJ, Ghysen A, Dambly-Chaudiere C. Genetic basis of the formation and identity of type I and type II neurons in Drosophila embryos. Development 1997;124:2819–28. Johnson JE. Numb and Numblike control cell number during vertebrate neurogenesis. Trends Neurosci 2003;26:395–6. Le Borgne R, Bardin A, Schweisguth F. The roles of receptor and ligand endocytosis in regulating Notch signaling. Development 2005;132:1751–62. Santolini E, Puri C, Salcini AE, Gagliani MC, Pelicci PG, Tacchetti C, et al. Numb is an endocytic protein. J Cell Biol 2000;151:1345–52. Smith CA, Dho SE, Donaldson J, Tepass U, McGlade CJ. The cell fate determinant Numb interacts with EHD/Rme-1 family proteins and has a role in endocytic recycling. Mol Biol Cell 2004;15:3698–708. Donaldson JG. Multiple roles for Arf6: sorting, structuring, and signaling at the plasma membrane. J Biol Chem 2003;278:41573–6. Berdnik D, Torok T, Gonzalez-Gaitan M, Knoblich JA. The endocytic protein alpha-Adaptin is required for Numb-mediated asymmetric cell division in Drosophila. Dev Cell 2002;3:221–31. O’Connor-Giles KM, Skeath JB. Numb inhibits membrane localization of Sanpodo, a four-pass transmembrane protein, to promote asymmetric divisions in Drosophila. Dev Cell 2003;5:231–43. Skeath JB, Doe CQ. Sanpodo and Notch act in opposition to Numb to distinguish sibling neuron fates in the Drosophila CNS. Development 1998;125:1857–65. Schweisguth F. Regulation of notch signaling activity. Curr Biol 2004;14:129–38. Lai EC. Protein degradation: four E3s for the Notch pathway. Curr Biol 2002;12:74–8. Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. J Biol Chem 2001;276:35847– 53. Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, et al. SEL-10 is an inhibitor of Notch signaling that targets Notch for ubiquitinmediated protein degradation. Mol Cell Biol 2001;21:7403–15. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998;67:425–79. Hicke L. Gettin’ down with ubiquitin: turning off cellsurface receptors, transporters and channels. Trends Cell Biol 1999;9:107–12. Bonifacino JS, Weissman AM. Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu Rev Cell Dev Biol 1998;14:19–57. McGill MA, McGlade CJ. Mammalian Numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. J Biol Chem 2003;278:23196–203. Xu T, Artavanis-Tsakonas S. Deltex, a locus interacting with the neurogenic genes, Notch, Delta and mastermind in Drosophila melanogaster. Genetics 1990;126:665–77. Busseau I, Diederich RJ, Xu T, Artavanis-Tsakonas S. A member of the Notch group of interacting loci, Deltex encodes a cytoplasmic basic protein. Genetics 1994;136:585–96. Diederich RJ, Matsuno K, Hing H, Artavanis-Tsakonas S. Cytosolic interaction between Deltex and Notch ankyrin repeats implicates Deltex in the Notch signaling pathway. Development 1994;120:473–81. Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, ArtavanisTsakonas S. Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development 1995;121:2633–44. Matsuno K, Eastman D, Mitsiades T, Quinn AM, Carcanciu ML, Ordentlich P, et al. Human Deltex is a conserved regulator of Notch signalling. Nat Genet 1998;19:74–8.

622

D. Luo et al. / Seminars in Cell & Developmental Biology 16 (2005) 612–622

[90] Takeyama K, Aguiar RC, Gu L, He C, Freeman GJ, Kutok JL, et al. The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity. J Biol Chem 2003;278:21930–7. [91] Kishi N, Tang Z, Maeda Y, Hirai A, Mo R, Ito M, et al. Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis. Int J Dev Neurosci 2001;19:21–35. [92] Jackson PK, Eldridge AG, Freed E, Furstenthal L, Hsu JY, Kaiser BK, et al. The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 2000;10:429–39. [93] Saurin AJ, Borden KL, Boddy MN, Freemont PS. Does this have a familiar RING? Trends Biochem Sci 1996;21:208–14. [94] Borden KL. RING domains: master builders of molecular scaffolds? J Mol Biol 2000;295:1103–12. [95] Matsuno K, Ito M, Hori K, Miyashita F, Suzuki S, Kishi N, et al. Involvement of a proline-rich motif and RING-H2 finger of Deltex in the regulation of Notch signaling. Development 2002;129:1049–59. [96] Aravind L. The WWE domain: a common interaction module in protein ubiquitination and ADP ribosylation. Trends Biochem Sci 2001;26:273–5. [97] Luo D, Rando TA. Overexpression of Deltex2 inhibits mouse muscle cell differentiation. Mol Biol Cell 2004;15:48a. [98] Izon DJ, Aster JC, He Y, Weng A, Karnell FG, Patriub V, et al. Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity 2002;16:231–43. [99] Yun TJ, Bevan MJ. Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development. J Immunol 2003;170:5834–41. [100] Cui XY, Hu QD, Tekaya M, Shimoda Y, Ang BT, Nie DY, et al. NB-3/Notch1 pathway via Deltex1 promotes neural progenitor cell differentiation into oligodendrocytes. J Biol Chem 2004;279:25858–65. [101] Hu QD, Ang BT, Karsak M, Hu WP, Cui XY, Duka T, et al. F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell 2003;115:163–75. [102] Yamamoto N, Yamamoto S, Inagaki F, Kawaichi M, Fukamizu A, Kishi N, et al. Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor. J Biol Chem 2001;276:45031–40. [103] Storck S, Delbos F, Stadler N, Thirion-Delalande C, Bernex F, Verthuy C, et al. Normal immune system development in mice lacking the Deltex-1 RING finger domain. Mol Cell Biol 2005;25:1437–45. [104] Gorman MJ, Girton JR. A genetic analysis of deltex and its interaction with the Notch locus in Drosophila melanogaster. Genetics 1992;131:99–112. [105] Fortini ME, Artavanis-Tsakonas S. The Suppressor of Hairless protein participates in Notch receptor signaling. Cell 1994;79:273–82. [106] Matsuno K, Go MJ, Sun X, Eastman DS, Artavanis-Tsakonas S. Suppressor of Hairless-independent events in Notch signaling imply novel pathway elements. Development 1997;124:4265–73. [107] Ramain P, Khechumian K, Seugnet L, Arbogast N, Ackermann C, Heitzler P. Novel Notch alleles reveal a Deltex-dependent pathway repressing neural fate. Curr Biol 2001;11:1729–38. [108] Hori K, Fostier M, Ito M, Fuwa TJ, Go MJ, Okano H, et al. Drosophila Deltex mediates Suppressor of Hairless-independent and late-endosomal activation of Notch signaling. Development 2004;131:5527–37. [109] Liu WH, Lai MZ. Deltex regulates T-cell activation by targeted degradation of active MEKK1. Mol Cell Biol 2005;25:1367–78. [110] Fostier M, Evans DA, Artavanis-Tsakonas S, Baron M. Genetic characterization of the Drosophila melanogaster Suppressor of deltex gene: A regulator of notch signaling. Genetics 1998;150:1477– 85.

[111] Cornell M, Evans DA, Mann R, Fostier M, Flasza M, Monthatong M, et al. The Drosophila melanogaster Suppressor of deltex gene, a regulator of the Notch receptor signaling pathway, is an E3 class ubiquitin ligase. Genetics 1999;152:567–76. [112] Mazaleyrat SL, Fostier M, Wilkin MB, Aslam H, Evans DA, Cornell M, et al. Down-regulation of Notch target gene expression by Suppressor of deltex. Dev Biol 2003;255:363–72. [113] Baron M, Aslam H, Flasza M, Fostier M, Higgs JE, Mazaleyrat SL, et al. Multiple levels of Notch signal regulation. Mol Membr Biol 2002;19:27–38. [114] Qiu L, Joazeiro C, Fang N, Wang HY, Elly C, Altman Y, et al. Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase. J Biol Chem 2000;275:35734–7. [115] Rotin D, Staub O, Haguenauer-Tsapis R. Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases. J Membr Biol 2000;176:1–17. [116] Sundaram M, Greenwald I. Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans. Genetics 1993;135:765–83. [117] Hubbard EJ, Wu G, Kitajewski J, Greenwald I. Sel-10, a negative regulator of Lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Genes Dev 1997;11:3182–93. [118] Gupta-Rossi N, Le Bail O, Gonen H, Brou C, Logeat F, Six E, et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. J Biol Chem 2001;276:34371–8. [119] Jager S, Schwartz HT, Horvitz HR, Conradt B. The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome. Proc Natl Acad Sci USA 2004;101:12549–54. [120] Tetzlaff MT, Yu W, Li M, Zhang P, Finegold M, Mahon K, et al. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein. Proc Natl Acad Sci USA 2004;101:3338–45. [121] Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, et al. Mouse Fbw7/Sel-10/Cdc4 is required for Notch degradation during vascular development. J Biol Chem 2004;279:9417–23. [122] Levitan D, Greenwald I. Facilitation of Lin-12-mediated signalling by Sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 1995;377:351–4. [123] Li J, Pauley AM, Myers RL, Shuang R, Brashler JR, Yan R, et al. SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production. J Neurochem 2002;82:1540–8. [124] Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998;14:59–88. [125] McEwen DG, Peifer M. Wnt signaling: Moving in a new direction. Curr Biol 2000;10:562–4. [126] Axelrod JD, Matsuno K, Artavanis-Tsakonas S, Perrimon N. Interaction between Wingless and Notch signaling pathways mediated by dishevelled. Science 1996;271:1826–32. [127] Zecchini V, Brennan K, Martinez-Arias A. An activity of Notch regulates JNK signalling and affects dorsal closure in Drosophila. Curr Biol 1999;9:460–9. [128] Tatsumi R, Anderson JE, Nevoret CJ, Halevy O, Allen RE. HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev Biol 1998;194:114–28. [129] Yablonka-Reuveni Z, Seger R, Rivera AJ. Fibroblast growth factor promotes recruitment of skeletal muscle satellite cells in young and old rats. J Histochem Cytochem 1999;47:23–42. [130] Polesskaya A, Seale P, Rudnicki MA. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell 2003;113:841–52.