Neural Crest Cells in Ocular Development

C H A P T E R

10 Neural Crest Cells in Ocular Development Sinu Jasrapuria-Agrawal and Peter Y. Lwigale Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA O U T L I N E Introduction

189

Neural Crest and Early Eye Development

191

Signaling Between NCC and the Optic Cup

192

Signaling Between NCC and the Lens

193

Signaling Between NCC and Ectoderm

194

Other Contribution of NCC to Ocular Tissues

194

INTRODUCTION Vertebrate eye development is a complex process that involves intricate interactions between the surface ectoderm, neuroectoderm, and mesenchymal cells of neural crest (NC) origin. Neural crest cells (NCC) that contribute to the ocular anlage migrate a relatively long distance from the neural tube into the presumptive eye region, also known as the periocular region. Cell tracking experiments using DiI [1],

Neural Crest Cells. DOI: http://dx.doi.org/10.1016/B978-0-12-401730-6.00011-9

Indirect Neural Crest Contribution to the Eye via Trigeminal and Ciliary Nerves 195 Neural Crest Related Ocular Defects

196

Conclusions and Perspectives

198

References

199

interspecies neural crest transplantation [2 5], or transgenesis [6] have mapped the NCC migrating from the region between the rostral diencephalon and the metencephalon to the periocular region (Figure 10.1A and B). NCC from the rostral diencephalic regions migrate between the ectoderm and the optic vesicles and later combine with NCC from the mesencephalic and metencephalic regions to form the periocular NCC (Figure 10.1C). Although NCC are generated along the axis of

189

© 2014 Elsevier Inc. All rights reserved.

190

10. NEURAL CREST CELLS IN OCULAR DEVELOPMENT

(A)

(B)

(C) NCC

M et en

Mesen

Dien nt

ov

e n Die

ov

Iv

e Mesen

oc Meten

FIGURE 10.1 Origin and migration of cranial NCC into the periocular region during eye development in chick. (A) At the 12-somite stage [7], NCC (green) originating from the neural tube region between the rostral diencephalon and metencephalon migrate laterally during the optic vesicle stage of eye development. The arrows represent populations from the diencephalic (red), mesencephalic (purple), and metencephalic (blue) regions. (B) At embryonic day 2, NCC from the three regions coalesce in the periocular region but avoid the invaginating optic vesicle and presumptive lens region. (C) Representation of a cross section through a rudimentary eye at E3 showing the lens vesicle and optic cup surrounded by NCC and ectoderm. ov, optic vesicle; nt, neural tube; e, ectoderm; oc, optic cup; lv, lens vesicle; NCC, neural crest cells in the periocular region.

the developing embryo, their ability to give rise to ocular structures diminishes towards the caudal regions [8]. The ability of cranial NCC to generate normal ocular structure has been linked to the lack of Hox gene function in the presumptive ocular neural crest territory, since ectopic expression of Hoxa2, -a3, or -b4 affects the formation of ocular structures [9,10]. Upon the formation of the rudimentary eye, the surface ectoderm gives rise to the lens vesicle and overlying ectoderm, and the neuroectoderm gives rise to the optic cup, whereas the periocular mesenchyme (consisting of the NCC and cranial mesoderm) fills in the space between the optic cup and ectoderm (Figure 10.1C). The rudimentary eye functions as the basic structure for eye development, which undergoes subsequent development to form the anterior segment (cornea, iris, lens, ciliary body, and trabecular meshwork), eyelids, retina, and the ocular blood vessels and muscles. With the exception of the lens and retina, NCC either give rise to or contribute to most of the ocular tissues [3,4]. As the NCC differentiate into ocular tissues, nerves originating from the trigeminal and ciliary ganglia, as well as the

oculomotor nerve, project into the developing eye and provide sensory, sympathetic, and parasympathetic innervation. Because the trigeminal and ciliary ganglia are comprised of neural crest-derived and ectodermal placode-derived neurons [11,12], a significant portion of ocular innervation can be considered an indirect contribution of NCC to the eye. During their migration into the periocular region, NCC express markers such as the neuronal carbohydrate epitope HNK-1 and the transcription factor Sox10. However, these markers are downregulated in the periocular region [2,13] as the NCC take on new identities that are crucial to their differentiation into various ocular tissues. The behavior of NCC as they migrate from the neural tube to the periocular region and their subsequent differentiation into ocular tissues is conserved between chick, mouse, and human (Figure 10.2) [14 17]. However, some differences exist between chick and mouse cornea development. During chick cornea development, two waves of NCC migration form, respectively, the endothelium and stroma of the cornea [16]. In mouse, these layers form

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

191

NEURAL CREST AND EARLY EYE DEVELOPMENT

Migration

Differentiation

Periocular region (B)

(A)

(C)

ocular muscle ey

e

ciliary body e

ov

i

lv

lens

c

oc sclera

CHICK

E1.5

E3

E7

MOUSE E9.5

E11.5

E16.5

HUMAN 28 days of gestation

5th week of gestation

5th month of gestation

FIGURE 10.2 Cranial neural crest behavior during eye development and differentiation into ocular tissue is conserved between chick, mouse, and human. Cranial neural crest behavior during eye development (A, B) and differentiation into ocular tissues (C) is conserved between chick, mouse and human. The relative times during development at which NCC (green) migrate into the presumptive ocular region, contribute to the mesenchyme of the rudimentary eye, and differentiate into various ocular tissues are indicated. ov, optic vesicle; e, ectoderm; oc, optic cup; lv, lens vesicle; NCC, neural crest cells in periocular region; ey, eyelids; c, cornea; i, iris.

from a single mass of NCC that migrate between the lens and ectoderm and eventually differentiate into cornea endothelium and stroma [14]. NCC are undifferentiated as they migrate and occupy the ocular region. Morphogenic and inductive processes that form the lens vesicle and optic cup localize NCC in the periocular region and provide migration and differentiation cues that instruct these cells to generate various ocular tissues. In this chapter, we summarize studies that have contributed to our current knowledge of the cellular and molecular mechanisms underlying neural crest contribution to the eye, and the ocular malformation associated with NCC.

NEURAL CREST AND EARLY EYE DEVELOPMENT NCC that migrate into the presumptive eye region prior to the formation of the lens and optic cup play a critical role in organizing the eye during early development. This was

evident from co-culture studies when NCC abolished expression of the lens-specific gene δ-crystallin by presumptive lens ectoderm [18]. These results were further confirmed in vivo when cranial neural tube ablation in chick resulted in the formation of ectopic lenses, which stained positive for Pax6 and δ-crystallin in the absence of neural crest. Subsequently, it was recognized that NCC suppress lens formation via transforming growth factor beta (TGF-β) signaling, which activates Smad3 and Wnt signaling to repress Pax6 in the non-lens-forming cranial ectoderm [19]. Thus, the intrinsic lens potential of the cranial ectoderm is restricted by NCC, which permit lens formation only in the NCfree zone at the interface between the optic vesicle and surface ectoderm. Formation of the lens in the NC-free zone is crucial for its subsequent alignment with the optic cup and critical for normal vision. Likewise, the developing eye is required for proper migration of NCC. Genetic ablation of the optic vesicles in chokh/rx3 eyeless zebrafish mutants prevents

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

192

10. NEURAL CREST CELLS IN OCULAR DEVELOPMENT

anterior migration of cranial NCC, resulting in defects in the neurocranium and orbits [20]. In addition, platelet-derived growth factor (PDGF) secreted by the optic vesicle regulates neural crest migration via their expression of platelet-derived growth factor receptor (PDGFR) that is modulated by miR140 [21]. Signaling between periocular mesenchyme and the optic cup is also involved in the formation of the retinal pigmented epithelium (RPE). When optic vesicle explants were cultured in the absence of the periocular mesenchyme, the RPE-specific gene Mitf and other markers were not expressed, and instead the neural retinaspecific gene Chx10 was ectopically expressed [22]. However, the RPE forms normally when mesenchyme-free optic vesicles are cultured in the presence of the TGF-β family member activin A [22]. Together, these studies indicate that signaling between the neural crest and optic vesicles is crucial for the early stages of eye development. Not only are these early interactions indispensible for ocular development but also essential for craniofacial development, since abnormalities in eye and craniofacial development are closely associated [23].

SIGNALING BETWEEN NCC AND THE OPTIC CUP NCC continue to surround the optic vesicle as it undergoes morphogenesis to form the optic cup but they avoid the anterior region where the lens vesicle detaches from the surface ectoderm (Figure 10.1C). Despite the loss of typical NCC markers such as Sox10 and HNK-1 [2,13] and their transition from mesenchymal to fibroblastic morphology, [24]. NCC remain relatively undifferentiated while they receive signals from the surrounding ocular tissues that determine their future identity. Signaling between the NCC and the optic cup is crucial for the formation of the anterior

segment and posterior structures such as the ocular muscles. The morphogen retinoic acid (RA) is a major signaling component of the optic cup, lens, and surface ectoderm [25]. Paracrine RA signaling via retinoic acid receptors (RAR-α/β/γ) expressed by the NCC regulates the expression of genes that are involved in directing NCC migration, proliferation, and differentiation. RA signaling impairs apoptosis of NCC and controls the expression of the transcription factors Pitx2, Foxc1, Eya2 [25 27] that are crucial for the proper patterning and development of the anterior segment. In humans, null mutations in Pitx2 and Foxc1 cause Axenfeld Rieger’s syndrome, a condition that includes dysgenesis of the anterior segment characterized by thickening of the corneal stroma, absence of the anterior chamber, and malformation of the iris [28,29]. Similar defects were observed in knockout mice lacking Pitx2 or Foxc1 [10,26]. Furthermore, Pitx2 acts upstream of Dkk2 to regulate canonical Wnt signaling [30], which feeds back into Pitx2 and maintains its expression [31]. Several Wnt genes and receptors are expressed in the anterior eye during development [22,32 34], but the function of Wnt signaling in the NCC is not clear. In culture, Wnt/β-catenin signaling promotes neural crest differentiation into melanoblasts, and their proliferation [35,36]. But in mice, the constitutive activation of β-catenin (Ctnnb1) in NCC promotes sensory neurogenesis in all cell lineages, including melanocytes [37]. In contrast, activation of β-catenin in zebrafish promotes formation of melanocytes but represses neural cell lineages [38]. This inconsistency is due to the fact that in mouse embryos, Wnt/β-catenin signaling controls sensory fate acquisition prior to formation of melanocyte lineage [39]. Since NCC do not differentiate into melanocytes or neurons in the ocular region, it is unlikely that Wnt/β-catenin signaling plays a similar role, and function remains a topic for future study.

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

SIGNALING BETWEEN NCC AND THE LENS

SIGNALING BETWEEN NCC AND THE LENS Lens ablation experiments have shown that the lens plays a crucial role during the formation of the cornea and development of the anterior segment [40 44]. These studies show that in the absence of the lens, NCC precociously migrate into the cornea-forming region, but fail to form the cornea endothelium and stroma, suggesting that the lens is involved in neural crest migration and/or differentiation. During development of the anterior segment, NCC migrate between the lens and overlaying ectoderm to form the cornea, while those that remain in the periocular region form the ciliary body, iris, trabecular meshwork, and also contribute to the pericytes of the ocular blood vessels and to the ocular muscles. Several studies have shown that TGF signaling from the lens is involved in NCC migration and subsequent development of the anterior segment. Disruption of TGF-β1 [45,46] or TGF-β2 [47 49] in mice via loss of function or overexpression leads to defective ocular development. Reduction in size of the cornea stroma [48] and absence of the corneal endothelium [49] suggest that lens-derived TGF signaling augments NCC migration. Not only do lens-derived signals augment NCC migration. The lens expresses Semaphorin3A (Sema3A), a secreted chemorepellent [50 52] that forms a barrier to ocular cells that express its receptor Neuropilin1 (Npn1). In chick, Sema3A is steadily expressed by the lens during ocular development whereas, expression of the Npn1 is downregulated by NCC that migrate between the ectoderm and lens to form the cornea endothelium and stroma, but maintained in the non-migratory NCC that contribute to the periocular tissues [13]. Therefore, the lens also plays a critical role in directing NCC migration and localizing them in regions where

193

they receive different signals to differentiate into various ocular tissues. In addition to guiding NCC migration, signaling by the lens is required during both the early and late stages of cornea development. Shortly after its formation, the lens vesicle induces the overlying ectoderm to secrete extracellular matrix (primary stroma), which acts as a substratum for neural crest migration during cornea development [16,53]. The primary stroma is rich in extracellular molecules such as collagen, fibronectin, laminin, and hyaluronan, which create a conducive environment for NCC migration [54 56]. In chick, a first wave of NCC migrates on the primary stroma adjacent to the lens and forms the inner most layer of the cornea (cornea endothelium). This is followed by a second wave of NCC migration into the primary stroma, which differentiates into stromal keratocytes. The keratocytes synthesize the matrix of the mature cornea that consists of collagens and proteoglycans that are vital to corneal transparency [57]. Together, the neural crest-derived cornea endothelium and stroma comprise 90% of the cornea. Signals from the lens are required for NCC differentiation into cornea endothelium and keratocytes. The cornea endothelium and keratocytes do not form in the absence of the lens [40,41]. Lack of differentiation of neural crest into corneal cells was also observed in mice after genetically ablating the lens by targeted deletion of the αA-crystallin gene [58]. Similarly, cavefish in which the lens degenerates shortly after the formation of the rudimentary eye show massive migration of periocular mesenchyme into the ocular region, but tissues of the anterior segment do not form. However, normal eye development is restored when surface fish lens is transplanted into the cavefish at the rudimentary eye stage [59]. The surface fish to cavefish lens transplantation studies suggest that signaling from the lens is required after the rudimentary eye stage for

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

194

10. NEURAL CREST CELLS IN OCULAR DEVELOPMENT

differentiation of NCC into tissues of the anterior segment.

SIGNALING BETWEEN NCC AND ECTODERM Periocular NCC also contribute to the mesenchyme of the eyelids, and in birds to skeletogenic condensations known as the scleral ossicles [3,4,60]. The formation of the eyelids and scleral ossicles is initiated by interactions between the NCC and periocular ectoderm. At the initiation of eyelid formation, the forkhead transcription factors foxc1, foxc2, and foxl2 are expressed in the neural crest mesenchyme of the presumptive eyelid buds [10,61]. Unlike foxc1 and foxc2, which are also expressed in the presumptive eyelid ectoderm, expression of foxl2 is restricted to the NCC. Eyelids do not form in foxl2-null mice, [62] and overexpression of Notch signaling via ectopic expression of the Notch1 intracellular domain in NCC downregulates foxl2 also resulting in the eyesopen at birth (EOB) phenotype [63]. Also the foxc1 and foxc2 knockout mice exhibit the EOB phenotype [10]. Furthermore, the EOB phenotype is observed in the absence of other genes expressed by NCC including Fgf10, bone morphogenetic protein 4 (BMP4), and Dkk2 [64]. Signaling between the NCC-derived Fgf10 and the Fgfr2 receptor in the ectoderm stimulates epithelial migration [65], promotes the expression of BMP4 in the NCC, and suppresses Wnt signaling via sfrp1 to maintain foxc2 [64]. Furthermore, it is possible that Pitx2 augmentation of Dkk2 in the NCC plays a similar role since Pitx2-null mice display the EOB phenotype [30]. These studies show that signaling between the NCC and periocular ectoderm are critical for the induction and elongation of eyelids during development. The scleral ossicles form a ring around the developing eye in avians, reptilians, and pisces [66]. Development of scleral ossicles in avians

is initiated by transient thickening of the ectoderm in the periocular region of the conjunctiva, which result in the formation of papillae that correspond to subsequent condensation of the subjacent NCC [67,68]. Ablation of papillae prior to the condensation of the NCC [69] or placement of a barrier between the ectoderm and NCC [70] prevents the formation of the scleral ossicles. Together, these studies suggest that epithelial mesenchymal interactions via a diffusible factor are required for the formation of scleral ossicles. In an effort to determine the nature of the signals involved in the epithelial mesenchymal interactions, a study by Franz-Odendaal [71] showed that shh is expressed in the papillae prior to NCC condensation, maintains its signal to the epithelium in a positive feed-back mechanism, and that inhibition of shh signaling in the papillae with cyclopamine prevented ossicle development. In a follow-up publication, Duench and Franz-Odendaal [72] identified the expression of Indian hedgehog (ihh) in the papillae during induction, and that of patched1 (ptc1), a receptor for shh, in the epithelium and mesenchyme during ossicle development. Inhibition of BMP via bead implantation adjacent to the papillae reduced the expression of ihh, suggesting that these pathways interact during development of the scleral ossicles [72]. Given that BMP and Hh interact during skeletal development, [72 74] and that ihh is involved in the development of neural crest-derived bones, [75] the two pathways may be involved in NCC differentiation into scleral ossicles.

OTHER CONTRIBUTION OF NCC TO OCULAR TISSUES The mesodermal component of the periocular mesenchyme gives rise to the ocular blood vessels and muscles [76]. NCC contribute to these tissues as pericytes and alpha smooth muscle-positive cells to the ocular blood

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

INDIRECT NEURAL CREST CONTRIBUTION TO THE EYE VIA TRIGEMINAL AND CILIARY NERVES

vessels, iris stroma, and eyelids [4,77]. NCC that contribute to the ocular blood vessels and iris stroma belong to the Npn1-positive population that resides adjacent to the optic cup [13], probably in response to vascular endothelial growth factor (VEGF) signaling from the optic cup. Pericytes (also known as vascular smooth muscle cells or mural cells) are contractile cells that wrap around the surface of the vascular tube. The signals involved in pericyte differentiation may originate from the ocular blood vessels since only the adjacent NCC form pericytes. NCC are recruited to the developing vasculature via PDGF and EGF signaling. Coculture of vascular endothelial cells with pericytes showed that pericyte migration, proliferation, and recruitment to the endothelial tube are dependent on the presence of endothelial cells and under the influence of PDGF and EGF signaling [78]. This study also showed that abrogation of both PDGF and EGF signaling in quail embryos prevented pericyte recruitment to developing vasculature resulting in increased vessel width and vascular hemorrhage due to decreased deposition of basement membrane. In chick, PDGF and PDGFRβ are expressed in the periocular region where ocular blood vessels form [79], suggesting that signaling between NCC and periocular vascular mesoderm plays a role during development of ocular blood vessels. NCC also contribute to myogenic structures of the eye, including the anterior surface of the presumptive iris, the trabecular meshwork and ciliary body of the iridocorneal angle, and stroma of the eyelids. All these tissues stain positive for the muscle marker α-SMA shortly after their formation [80,81]. Similarly, these tissues express members of the TGF-β superfamily such as Activin, BMP4/7 that are involved in myogenesis [45,80 82]. Knockout mice lacking either BMP4 or BMP7 show diminished ocular development, but due to early embryonic lethality they cannot be studied for events that occur during late ocular development [83].

195

Contribution to the connective tissues of the extraocular muscles occurs in the medialposterior regions of the eye [3,84]. During early eye development, the presumptive extraocular muscle mesoderm is intermingled with NCC that form the sclera. Experiments in which the trunk paraxial mesoderm was grafted into the cranial region showed that the grafted mesoderm could form extraocular muscles indicating that NCC direct myogenesis in this region [84]. Also, neural crest ablation experiments suggest that interactions between NCC and mesoderm are required for proper extraocular muscle development. Genetic ablation of cranial NCC in zebrafish using morpholinos against Sox10 or FoxD3 results in malformation of several tissues including the extraocular muscles [85]. Its also been suggested that RA signaling in the NCC is required for normal positioning of the extraocular muscles [26]. Although Pitx2 is downstream of RA signaling, its expression by NCC is not required for proper development of extraocular muscles [27].

INDIRECT NEURAL CREST CONTRIBUTION TO THE EYE VIA TRIGEMINAL AND CILIARY NERVES Nerves that innervate the ocular tissues (except the retina) originate from the trigeminal and ciliary ganglia. Both ganglia are derived from neural crest and ectodermal placode cells [11,12]. The NCC that contribute to the trigeminal and ciliary ganglia migrate from the neural tube region encompassing the mesencephalon and metencephalon [11,86]. Although this region overlaps with the origin of the NCC, the trigeminal NCC cease to migrate shortly after they exit from the neural tube and intermix with the trigeminal placode that ingress from the overlying ectoderm [87,88]. NCC that give rise to ciliary neurons

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

196

10. NEURAL CREST CELLS IN OCULAR DEVELOPMENT

originate from the mesencephalic region of the neural tube, migrate ventral-laterally, and aggregate close to the ophthalmic branch of the trigeminal ganglion and oculomotor nerve located in the posterior eye region [12,89,90]. The NCC within these two ganglia differentiate into neurons and glia, but the placode cells form only neurons. The trigeminal ganglion provides sensory innervation to the cornea, iris, extraocular muscles, and eyelids [86,91 93]. Sensory nerves that innervate the face and the eye project from the ophthalmic and maxillary branches of the trigeminal ganglion [84,94]. As observed during NCC migration, Sema3A/ Npn1 signaling regulates trigeminal sensory nerve projection into the developing cornea [52,95]. Other studies have shown that RoboSlit signaling is also involved in guiding trigeminal nerves during cornea innervation [96]. Of particular interest to neural crest contribution to the eye is the selective innervation of the cornea by neural crest-derived trigeminal nerves with no contribution from the placodederived nerves. Experiments using quail-chick chimeras and tissue ablation showed that despite the dual composition of the trigeminal ganglion by both neural crest- and placodederived cells, only the neural crest-derived nerves innervate the cornea [86]. Sensory nerves in the cornea secrete neural transmitters including acetylcholine, substance P, and calcitonin gene-related peptide, which stimulate proliferation of cells in the cornea epithelium [97,98]. Loss of sensory innervation of the cornea results in a vision-threatening clinical condition known as neurotrophic keratopathy, characterized by reduced corneal sensation, corneal epithelial defects, and perforation of the stroma [97,99]. The ciliary ganglion provides parasympathetic innervation to the iris, ciliary muscle, extraocular muscles, and eyelids [100,101]. Ciliary innervation of the iris regulates the amount of light entering the eye by controlling

pupil dilation and constriction. Innervation of the ciliary muscle plays a role in visual acuity by regulating lens accommodation. Damage to the ciliary ganglion due to disease or trauma causes a neurological condition known as tonic pupil (Adie’s syndrome), whereby the pupil does not respond to light and lens accommodation is slow [102,103].

NEURAL CREST RELATED OCULAR DEFECTS Anterior segment dysgenesis (ASD) refers to anomalies in the structure of the mature anterior segment of the eye caused by developmental disorders associated with the NCC, lens, and optic cup. Clinical screening of patients with ocular defects and genetic analysis of the developing eye have lead to the identification of several genes (mainly transcription factors) that act as molecular cues during the patterning of NCC. ASD affects multiple ocular tissues, making classification of disorders difficult due to overlap in clinical features. To avoid the use of different clinical terms to describe the same condition [104], features of malformation affecting each ocular tissue in the anterior segment have been characterized. Most of the abnormalities due to ASD are associated with elevated intraocular pressure, increased incidence of glaucoma, and loss of corneal transparency. They fall into a broad category of panocular diseases described in Table 10.1. Different gene disorders cause overlapping phenotypes, suggesting that ASD genes act via similar pathways and could be upstream or downstream target of each other. For example, Pitx2 binds Foxc1 and represses the activation of putative Foxc1 target genes [108]. Similarly, FGF19 is regulated by Foxc1, and in zebrafish reduced FGF19 activity leads to ASD [109]. Since NCC receive signals from other ocular tissues, genes associated with development of

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

197

NEURAL CREST RELATED OCULAR DEFECTS

TABLE 10.1

Ocular Defects Associated with NCC

Defects

Clinical Features

Associated Genes

ANTERIOR SEGMENT DYSGENESIS (ASD) Aniridia Corneal opacity, absence of iris, ciliary body may PAX6 [70,97] be hypoplastic. Increased corneal thickness in some cases. Anterior Segment Mesenchymal Dysgenesis

Iris adhesions to the cornea and corneal opacity. Corneas are dysplastic (abnormal migration or function of NCC). Lens opacities. Elevated intraocular pressure is usually not present.

PITX3 [97], FOXE3 [105], (TGF-β signaling) [40 44], MAF [106]

Axenfeld-Rieger Syndrome

Polycoria (more than 1 pupil), abnormal iris, thickening of corneal stroma, and absence of anterior chamber.

BMP signaling [70], PITX2 [30], FOXC1 [2], PAX6 [70,97], FOXE32

Cataract

Clouding of the lens.

PAX6 [70,97], MAF [106], PITX3 [106]

Coloboma

Missing pieces from ocular tissues (iris, ciliary body, lens), appear as gap/notches. Associated with microphthalmia.

PAX6 [70,97]

Congenital Primary Aphakia Absence of lens, iris, ciliary body, trabecular meshwork.

FOXE3 [2], PITX2 [30]

Iris hypoplasia/ Iridogoniodysgenesis (IRID1)

Iris hypoplasia, Abnormal angle iris strands to trabecular meshwork, cornea synechiae.

PITX2 [30], FOXC1 [2]

Microphthalmia/ Anophthalmia

Eyeballs are abnormally small. Associated with coloboma, cataract and microcornea.

MAF [106], PAX6 [70 97]

Peters Anomaly

Corneal opacity (with iris/lens adhesion), Pupil (polycoria), abnormal iris, cornea synechiae.

PITX2 [30], PAX6 [70 97], FOXC12, CYP1B1 [107]

Primary congenital glaucoma (PCG)

Abnormal iris, cornea (synechiae).

CYP1B1 [107]

Pupil does not respond to light and lens accommodation is slow, due to defects in the ciliary ganglion.

ND

Blepharophimosis, ptosis and epicanthus inversus syndrome (BPES)

Eyelid defects, poor eyelid closure, absence of levator smooth muscles. Palpebral fissures (distance between upper and lower eyelids) is small.

FOXL2 (Notch signaling) [58]

Eyelids open at birth (EOB)

Poor eyelid closure.

FOXL2 (Notch signaling) [58] Dkk2 (Wnt signaling) [30,60] Fgf10, Fgf2 (BMP signaling) [60]

Neurotrophic keratitis [87,89]

Reduced corneal sensation, corneal epithelial defects, neovascularization, poor corneal healing, perforation/melting of the stroma due to the impairment of trigeminal ganglion.

ND

OTHER DISEASE Adie’s syndrome [92,93]

ND, Not determined.

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

198

10. NEURAL CREST CELLS IN OCULAR DEVELOPMENT

the lens or optic cup may cause ASD through regulation of ASD-related transcription factors. Mutations affecting TGF-β signaling in the lens cause malformations similar to ASD [28,40,47]. In addition, the lens-specific genes MAF and Pitx3 cause ASD and induce cataract formation. Loss of Pax6, which is required for lens development, affects neural crest migration and differentiation, resulting in ASD [110]. Other neural crest-related ocular defects affect specific tissues. For example, aberrant expression of Notch1, which is crucial for proper expression of Foxl2 in the periocular mesenchyme causes reduced eyelid size or blepharophimosis syndrome [63]. Similar defects in Foxl2 in mouse cause EOB [63]. Malformation of the Trigeminal ganglion leads to absence of corneal nerves resulting in corneal anesthesis and melting of the stroma associated with neurotrophic keratitis [111]. Similarly, malformation or loss of the ciliary nerves affects the iris and accommodation of the lens and causes Adie’s syndrome [102,103].

CONCLUSIONS AND PERSPECTIVES Since the early classical experiments revealed the contribution of neural crest mesenchyme to ocular tissues, substantial progress has been made in elucidating the mechanisms involved in the generation of multiple ocular tissues for these multipotent cells. The fact that misregulation and mutation of genes causes ocular defects in different animal models provides further evidence that the timing of neural crest migration and interaction with the developing lens, retina, and ectoderm are crucial for proper differentiation into various ocular tissues. So far, the generation of various transgenic animal models, screening for modifier genes, characterization of regulatory elements, in conjunction with the identification of key players such as the RA, TGF-β, BMP, and

Wnt signaling pathways, and transcription factors such as Pax6, Pitx3, and Foxc, have all contributed to our understanding of NCC development. However, questions remain about mechanisms that control NCC differentiation into specific ocular tissues such as the cornea and stroma of the iris. Future studies will benefit from newly available transgenic lines and data analysis by ChIP-Seq, RNA-Seq, and Mass Spec. Increasing the list of target genes and specific binding partners will provide better characterization of the genetic and transcriptional regulatory networks crucial for NCC differentiation, which in turn will increase our understanding of eye development and provide valuable insight for therapies aimed at treating ocular disorders and diseases. NCC-derived cornea endothelium and stromal keratocytes are quiescent in the adult, but damage and disease render them dysfunctional. With increasing knowledge, there is enormous potential in using stem cells to repair neural crest-derived ocular tissues. The derivation of keratocytes from human embryonic stem cells (hESCs) provides a valuable tool for studying human cornea development and associated disease [112]. Generation of cornea endothelial cells and keratocytes from neural crest or pluripotent stem cells has tremendous implications for tissue-engineering and cell-based therapies for treatment of ocular diseases. The good news is that neural crest function in ocular development is conserved across species despite differences in how their eyes form. Therefore, future studies utilizing a combination of classical techniques and new approaches including genomic and cell biological studies that integrate the cell-intrinsic molecular mechanisms and interactions can be applied to the popular model organisms (chick, mouse, Xenopus, and zebrafish) for developmental biology research. Finally, the evolution of the eye is a subject of significant interest. These studies address

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

REFERENCES

similarities and diversions between eyes ranging from simple photoreceptors that sense light to complex multicellular organs of vision. In this chapter, we have discussed the roles of NCC in vertebrate eye development. But the role of NCC in the evolution of the eye remains an open subject for investigation. Interestingly, some invertebrates such as the squid form complex eyes that are homologous to vertebrates despite the absence of NCC. Therefore, some interesting questions arise: How does the squid form complex ocular structure such as the cornea, and iris, in the absence of NCC? Do squid have cells that perform signaling roles similar to those of NCC during vertebrate ocular development? These questions will increase our understanding of whether the molecular mechanisms and cellular interactions of NCC are a vertebrate invention or if they already existed in non-neural crest cells of the invertebrate cranial mesenchyme.

References [1] Trainor PA, Tam PPL. Cranial paraxial mesoderm and neural crest cells of the mouse embryo—codistribution in the craniofacial mesenchyme but distinct segregation in branchial arches. Development 1995;121(8):2569 82. [2] Mears AJ, Jordan T, Mirzayans F, Dubois S, Kume T, Parlee M, et al. Mutations of the forkhead/wingedhelix gene, FKHL7, in patients with Axenfeld Rieger anomaly. Am J Hum Genet 1998;63(5):1316 28. [3] Johnston MC, Noden DM, Hazelton RD, Coulombre JL, Coulombre AJ. Origins of avian ocular and periocular tissues. Exp Eye Res 1979;29(1):27 43. [4] Creuzet S, Vincent C, Couly G. Neural crest derivatives in ocular and periocular structures. Int J Dev Biol 2005;49(2 3):161 71. [5] Lwigale PY, Cressy PA, Bronner-Fraser M. Corneal keratocytes retain neural crest progenitor cell properties. Dev Biol 2005;288(1):284 93. [6] Nishimura DY, Swiderski RE, Alward WL, Searby CC, Patil SR, Bennet SR, et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet 1998;19(2):140 7. [7] Hamburger V, Hamilton HL. A series of normal stages in the development of the chick embryo. J Morphol 1951;88(1):49 92.

199

[8] Nishimura DY, Searby CC, Alward WL, Walton D, Craig JE, Mackey DA, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 2001;68(2):364 72. [9] Smith RS, Zabaleta A, Kume T, Savinova OV, Kidson SH, Martin JE, et al. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet 2000;9(7):1021 32. [10] Kume T, Deng KY, Winfrey V, Gould DB, Walter MA, Hogan BL. The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell 1998;93(6):985 96. [11] D’Amico-Martel A, Noden DM. Contributions of placodal and neural crest cells to avian cranial peripheral ganglia. Am J Anat 1983;166(4):445 68. [12] Lee VM, Sechrist JW, Luetolf S, Bronner-Fraser M. Both neural crest and placode contribute to the ciliary ganglion and oculomotor nerve. Dev Biol 2003;263 (2):176 90. [13] Lwigale PY, Bronner-Fraser M. Semaphorin3A/neuropilin-1 signaling acts as a molecular switch regulating neural crest migration during cornea development. Dev Biol 2009;336(2):257 65. [14] Pei YF, Rhodin JA. The prenatal development of the mouse eye. Anat Rec 1970;168(1):105 25. [15] Hoar RM. Embryology of the eye. Environ Health Perspect 1982;44:31 4. [16] Hay ED, Revel JP. Fine structure of the developing avian cornea. Monogr Dev Biol 1969;1:1 144. [17] Sowden JC. Molecular and developmental mechanisms of anterior segment dysgenesis. Eye 2007;21 (10):1310 8. [18] Bailey AP, Bhattacharyya S, Bronner-Fraser M, Streit A. Lens specification is the ground state of all sensory placodes, from which FGF promotes olfactory identity. Dev Cell 2006;11(4):505 17. [19] Grocott T, Johnson S, Bailey AP, Streit A. Neural crest cells organize the eye via TGF-beta and canonical Wnt signalling. Nat Commun 2011;2:265. [20] Langenberg T, Kahana A, Wszalek JA, Halloran MC. The eye organizes neural crest cell migration. Dev Dyn 2008;237(6):1645 52. [21] Eberhart JK, He X, Swartz ME, Yan YL, Song H, Boling TC, et al. MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis. Nat Genet 2008;40(3):290 8. [22] Fuhrmann S, Levine EM, Reh TA. Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick. Development 2000;127(21):4599 609. [23] Kish PE, Bohnsack B, Gallina D, Kasprick DS, Kahana A. The eye as an organizer of craniofacial development. Genesis 2011;49(4):222 30.

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

200

10. NEURAL CREST CELLS IN OCULAR DEVELOPMENT

[24] Bard JB, Hay ED. The behavior of fibroblasts from the developing avian cornea. Morphology and movement in situ and in vitro. J Cell Biol 1975;67 (2Pt.1):400 18. [25] Matt N, Dupe V, Garnier JM, Dennefeld C, Chambon P, Mark M, et al. Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells. Development 2005;132(21):4789 800. [26] Matt N, Ghyselinck NB, Pellerin I, Dupe V. Impairing retinoic acid signalling in the neural crest cells is sufficient to alter entire eye morphogenesis. Dev Biol 2008;320(1):140 8. [27] Evans AL, Gage PJ. Expression of the homeobox gene Pitx2 in neural crest is required for optic stalk and ocular anterior segment development. Hum Mol Genet 2005;14(22):3347 59. [28] Chang TC, Summers CG, Schimmenti LA, Grajewski AL. Axenfeld Rieger syndrome: new perspectives. Br J Ophthalmol 2012;96(3):318 22. [29] Reis LM, Tyler RC, Volkmann Kloss BA, Schilter KF, Levin AV, Lowry RB, et al. PITX2 and FOXC1 spectrum of mutations in ocular syndromes. Eur J Hum Genet 2012;20(12):1224 33. [30] Gage PJ, Qian M, Wu D, Rosenberg KI. The canonical Wnt signaling antagonist DKK2 is an essential effector of PITX2 function during normal eye development. Dev Biol 2008;317(1):310 24. [31] Zacharias AL, Gage PJ. Canonical Wnt/beta-Catenin signaling is required for maintenance but not activation of Pitx2 expression in neural crest during eye development. Dev Dyn 2010;239(12):3215 25. [32] Fokina VM, Frolova EI. Expression patterns of Wnt genes during development of an anterior part of the chicken eye. Dev Dyn 2006;235(2):496 505. [33] Jin EJ, Burrus LW, Erickson CA. The expression patterns of Wnts and their antagonists during avian eye development. Mech Dev 2002;116(1 2):173 6. [34] Fuhrmann S. Wnt signaling in eye organogenesis. Organogenesis 2008;4(2):60 7. [35] Dunn KJ, Williams BO, Li Y, Pavan WJ. Neural crestdirected gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse development. Proc Natl Acad Sci USA 2000;97:10050 5. [36] Jin EJ, Erickson CA, Takada S, Burrus LW. Wnt and BMP signaling govern lineage segregation of melanocytes in the avian embryo. Dev Biol 2001;233 (1):22 37. [37] Lee HY, Kleber M, Hari L, Brault V, Suter U, Taketo MM, et al. Instructive role of Wnt/beta-catenin in sensory fate specification in neural crest stem cells. Science 2004;303(5660):1020 3.

[38] Dorsky RI, Moon RT, Raible DW. Control of neural crest cell fate by the Wnt signalling pathway. Nature 1998;396(6709):370 3. [39] Hari L, Miescher I, Shakhova O, Suter U, Chin L, Taketo M, et al. Temporal control of neural crest lineage generation by Wnt/beta-catenin signaling. Development 2012;139(12):2107 17. [40] Beebe DC, Coats JM. The lens organizes the anterior segment: specification of neural crest cell differentiation in the avian eye. Dev Biol 2000;220 (2):424 31. [41] Zak NB, Linsenmayer TF. Analysis of corneal development with monoclonal antibodies. I. Differentiation in isolated corneas. Dev Biol 1985;108(2):443 54. [42] Zinn KM. Changes in corneal ultrastructure resulting from early lens removal in the developing chick embryo. Invest Ophthalmol 1970;9(3):165 82. [43] Genis-Galvez JM. Role of the lens in the morphogenesis of the iris and cornea. Nature 1966;210 (5032):209 10. [44] Genis-Galvez JM, Santos-Gutierrez L, Rios-Gonzalez A. Causal factors in corneal development: an experimental analysis in the chick embryo. Exp Eye Res 1967;6(1):48 56. [45] Flugel-Koch C, Ohlmann A, Piatigorsky J, Tamm ER. Disruption of anterior segment development by TGFbeta1 overexpression in the eyes of transgenic mice. Dev Dyn 2002;225(2):111 25. [46] Reneker LW, Silversides DW, Xu L, Overbeek PA. Formation of corneal endothelium is essential for anterior segment development—a transgenic mouse model of anterior segment dysgenesis. Development 2000;127(3):533 42. [47] Ittner LM, Wurdak H, Schwerdtfeger K, Kunz T, Ille F, Leveen P, et al. Compound developmental eye disorders following inactivation of TGFbeta signaling in neural-crest stem cells. J Biol 2005;4(3):11. [48] Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, et al. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 1997;124(13):2659 70. [49] Saika S, Liu CY, Azhar M, Sanford LP, Doetschman T, Gendron RL, et al. TGFbeta2 in corneal morphogenesis during mouse embryonic development. Dev Biol 2001;240(2):419 32. [50] Chilton JK, Guthrie S. Cranial expression of class 3 secreted semaphorins and their neuropilin receptors. Dev Dyn 2003;228(4):726 33. [51] Giger RJ, Wolfer DP, De Wit GM, Verhaagen J. Anatomy of rat semaphorin III/collapsin-1 mRNA expression and relationship to developing nerve tracts

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

201

REFERENCES

[52]

[53] [54]

[55]

[56]

[57] [58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

during neuroembryogenesis. J Comp Neurol 1996;375 (3):378 92. Lwigale PY, Bronner-Fraser M. Lens-derived Semaphorin3A regulates sensory innervation of the cornea. Dev Biol 2007;306(2):750 9. Hay ED. Development of the vertebrate cornea. Int Rev Cytol 1980;63:263 322. Coulombre AJ, Coulombre JL. Lens development. I. Role of the lens in eye growth. J Exp Zool 1964;156:39 47. Toole BP, Trelstad RL. Hyaluronate production and removal during corneal development in the chick. Dev Biol 1971;26(1):28 35. Fitch JM, Birk DE, Linsenmayer C, Linsenmayer TF. Stromal assemblies containing collagen types IV and VI and fibronectin in the developing embryonic avian cornea. Dev Biol 1991;144(2):379 91. Hassell JR, Birk DE. The molecular basis of corneal transparency. Exp Eye Res 2010;91(3):326 35. Kaur S, Key B, Stock J, McNeish JD, Akeson R, Potter SS. Targeted ablation of alpha-crystallin-synthesizing cells produces lens-deficient eyes in transgenic mice. Development 1989;105(3):613 9. Yamamoto Y, Jeffery WR. Central role for the lens in cave fish eye degeneration. Science 2000;289 (5479):631 3. Fyfe DM, Hall BK. The origin of the ectomesenchymal condensations which precede the development of the bony scleral ossicles in the eyes of embryonic chicks. J Embryol Exp Morphol 1983;73:69 86. Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/ epicanthus inversus syndrome. Nat Genet 2001;27 (2):159 66. Uda M, Ottolenghi C, Crisponi L, Garcia JE, Deiana M, Kimber W, et al. Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum Mol Genet 2004;13 (11):1171 81. Zhang Y, Kao WW, Pelosi E, Schlessinger D, Liu CY. Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis. J Cell Sci 2011;124(Pt 15):2561 72. Huang J, Dattilo LK, Rajagopal R, Liu Y, Kaartinen V, Mishina Y, et al. FGF-regulated BMP signaling is required for eyelid closure and to specify conjunctival epithelial cell fate. Development 2009;136 (10):1741 50. Tao H, Shimizu M, Kusumoto R, Ono K, Noji S, Ohuchi H. A dual role of FGF10 in proliferation and

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

coordinated migration of epithelial leading edge cells during mouse eyelid development. Development 2005;132(14):3217 30. Watanabe K, Bruder SP, Caplan AI. Transient expression of type II collagen and tissue mobilization during development of the scleral ossicle, a membranous bone, in the chick embryo. Dev Dyn 1994;200 (3):212 26. Murray PD. The development of the conjunctival papillae and of the scleral bones in the embryo chick. J Anat 1943;77(Pt 3):225 40.2. Coulombre AJ, Coulombre JL. The skeleton of the eye. I. Conjunctival papillae and scleral ossicles. Dev Biol 1962;5:382 401. Coulombre AJ, Coulombre JL. The skeleton of the eye. II. Overlap of the scleral ossicles of the domestic fowl. Dev Biol 1973;33(2):257 67. Pinto CB, Hall BK. Toward an understanding of the epithelial requirement for osteogenesis in scleral mesenchyme of the embryonic chick. J Exp Zool 1991;259 (1):92 108. Franz-Odendaal TA. Toward understanding the development of scleral ossicles in the chicken, Gallus gallus. Dev Dyn 2008;237(11):3240 51. Duench K, Franz-Odendaal TA. BMP and Hedgehog signaling during the development of scleral ossicles. Dev Biol 2012;365(1):251 8. Bitgood MJ, McMahon AP. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell cell interaction in the mouse embryo. Dev Biol 1995;172 (1):126 38. Kim HJ, Rice DP, Kettunen PJ, Thesleff I. FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development 1998;125 (7):1241 51. Abzhanov A, Rodda SJ, McMahon AP, Tabin CJ. Regulation of skeletogenic differentiation in cranial dermal bone. Development 2007;134 (17):3133 44. Couly GF, Coltey PM, Le Douarin NM. The developmental fate of the cephalic mesoderm in quail-chick chimeras. Development 1992;114(1):1 15. Etchevers HC, Vincent C, Le Douarin NM, Couly GF. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 2001;128(7):1059 68. Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood 2010;116 (22):4720 30.

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

202

10. NEURAL CREST CELLS IN OCULAR DEVELOPMENT

[79] Kwiatkowski S, Munjaal RP, Lee T, Lwigale PY. Expression of pro- and anti-angiogenic factors during the formation of the periocular vasculature and development of the avian cornea. Dev Dyn 2013;242 (6):738 51. [80] Jensen AM. Potential roles for BMP and Pax genes in the development of iris smooth muscle. Dev Dyn 2005;232(2):385 92. [81] Link BA, Nishi R. Development of the avian iris and ciliary body: the role of activin and follistatin in coordination of the smooth-to-striated muscle transition. Dev Biol 1998;199(2):226 34. [82] Zhao S, Chen Q, Hung FC, Overbeek PA. BMP signaling is required for development of the ciliary body. Development 2002;129(19):4435 42. [83] Jena N, Martin-Seisdedos C, McCue P, Croce CM. BMP7 null mutation in mice: developmental defects in skeleton, kidney, and eye. Exp Cell Res 1997;230 (1):28 37. [84] Noden DM. Patterning of avian craniofacial muscles. Dev Biol 1986;116(2):347 56. [85] Bohnsack BL, Gallina D, Thompson H, Kasprick DS, Lucarelli MJ, Dootz G, et al. Development of extraocular muscles requires early signals from periocular neural crest and the developing eye. Arch Ophthalmol 2011;129(8):1030 41. [86] Lwigale PY. Embryonic origin of avian corneal sensory nerves. Dev Biol 2001;239(2):323 37. [87] Stark MR, Sechrist J, Bronner-Fraser M, Marcelle C. Neural tube-ectoderm interactions are required for trigeminal placode formation. Development 1997;124 (21):4287 95. [88] Shiau CE, Lwigale PY, Das RM, Wilson SA, Bronner-Fraser M. Robo2-Slit1 dependent cell cell interactions mediate assembly of the trigeminal ganglion. Nat Neurosci 2008;11(3):269 76. [89] Narayanan CH, Narayanan Y. Determination of the embryonic origin of the mesencephalic nucleus of the trigeminal nerve in birds. J Embryol Exp Morphol 1978;43:85 105. [90] D’Amico-Martel A. Temporal patterns of neurogenesis in avian cranial sensory and autonomic ganglia. Am J Anat 1982;163(4):351 72. [91] Fackelmann K, Nouriani A, Horn AK, ButtnerEnnever JA. Histochemical characterisation of trigeminal neurons that innervate monkey extraocular muscles. Prog Brain Res 2008;171:17 20. [92] Kessler JA, Bell WO, Black IB. Interactions between the sympathetic and sensory innervation of the iris. J Neurosci 1983;3(6):1301 7.

[93] Nakamura A, Hayakawa T, Kuwahara S, Maeda S, Tanaka K, Seki M, et al. Morphological and immunohistochemical characterization of the trigeminal ganglion neurons innervating the cornea and upper eyelid of the rat. J Chem Neuroanat 2007; 34(3-4):95 101. [94] Marfurt CF. The somatotopic organization of the cat trigeminal ganglion as determined by the horseradish peroxidase technique. Anat Rec 1981;201(1):105 18. [95] Kubilus JK, Linsenmayer TF. Developmental guidance of embryonic corneal innervation: roles of Semaphorin3A and Slit2. Dev Biol 2010;344(1):172 84. [96] Schwend T, Lwigale PY, Conrad GW. Nerve repulsion by the lens and cornea during cornea innervation is dependent on Robo-Slit signaling and diminishes with neuron age. Dev Biol 2012;363 (1):115 27. [97] Cavanagh HD, Colley AM. The molecular basis of neurotrophic keratitis. Acta Ophthalmol Suppl 1989;192:115 34. [98] Mishima S. The effects of the denervation and the stimulation of the sympathetic and trigeminal nerve on the mitotic rate of the corneal epithelium in the rabbit. Jpn J Ophthalmol 1957;1:65 73. [99] Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye 2003;17(8):989 95. [100] Jaeger RJ, Benevento LA. A horseradish peroxidase study of the innervation of the internal structures of the eye. Evidence for a direct pathway. Invest Ophthalmol Vis Sci 1980;19(6):575 83. [101] Neuhuber W, Schrodl F. Autonomic control of the eye and the iris. Auton Neurosci 2011;165(1):67 79. [102] Thompson HS. Adie’s syndrome: some new observations. Trans Am Ophthalmol Soc 1977;75:587 626. [103] Perkin GD. Neuro-ophthalmological syndromes for neurologists. J Neurol Neurosurg Psychiatry 2004;75 (Suppl 4):20 3. [104] Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A review of anterior segment dysgeneses. Sur Ophthalmol 2006;51(3):213 31. [105] Semina EV, Brownell I, Mintz-Hittner HA, Murray JC, Jamrich M. Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet 2001;10(3):231 6. [106] Semina EV, Murray JC, Reiter R, Hrstka RF, Graw J. Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice. Hum Mol Genet 2000;9(11):1575 85.

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE

REFERENCES

[107] Sitorus R, Ardjo SM, Lorenz B, Preising M. CYP1B1 gene analysis in primary congenital glaucoma in Indonesian and European patients. J Med Genet 2003;40(1):e9. [108] Berry FB, Lines MA, Oas JM, Footz T, Underhill DA, Gage PJ, et al. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld Rieger syndrome and anterior segment dysgenesis. Hum Mol Genet 2006;15 (6):905 19. [109] Tamimi Y, Skarie JM, Footz T, Berry FB, Link BA, Walter MA. FGF19 is a target for FOXC1 regulation in ciliary body-derived cells. Hum Mol Genet 2006;15(21):3229 40.

203

[110] Thaung C, West K, Clark BJ, McKie L, Morgan JE, Arnold K, et al. Novel ENU-induced eye mutations in the mouse: models for human eye disease. Hum Mol Genet 2002;11(7):755 67. [111] Muller LJ, Vrensen GF, Pels L, Cardozo BN, Willekens B. Architecture of human corneal nerves. Invest Ophthalmol Vis Sci 1997;38(5):985 94. [112] Chan AA, Hertsenberg AJ, Funderburgh ML, Mann MM, Du Y, Davoli KA, et al. Differentiation of human embryonic stem cells into cells with corneal keratocyte phenotype. PloS One 2013;8(2): e56831.

II. NEURAL CREST CELL DIFFERENTIATION AND DISEASE