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Neural Crest Derivatives in Ocular Development: Discerning the Eye of the Storm Antionette L

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Neural Crest Derivatives in Ocular Development: Discerning the Eye of the Storm Antionette L Review Neural Crest Derivatives in Ocular Development: Discerning the Eye of the Storm Antionette L. Williams and Brenda L. Bohnsack* Neural crest cells (NCCs) are vertebrate-specific transient, multipotent, on congenital eye diseases associated with anterior segment defects and the migratory stem cells that play a crucial role in many aspects of embryonic interplay between three prominent molecules, PITX2, CYP1B1, and retinoic development. These cells emerge from the dorsal neural tube and acid, which act in concert to specify a population of neural crest-derived subsequently migrate to different regions of the body, contributing to the mesenchymal progenitors for migration and differentiation, to give rise to formation of diverse cell lineages and structures, including much of the distinct anterior segment tissues. We also describe recent findings implicating peripheral nervous system, craniofacial skeleton, smooth muscle, skin this stem cell population in ocular coloboma formation, and introduce recent pigmentation, and multiple ocular and periocular structures. Indeed, evidence suggesting the involvement of NCCs in optic fissure closure and abnormalities in neural crest development cause craniofacial defects and vascular development. ocular anomalies, such as Axenfeld-Rieger syndrome and primary congenital glaucoma. Thus, understanding the molecular regulation of neural crest Birth Defects Research (Part C) 105:87–95, 2015. development is important to enhance our knowledge of the basis for VC 2015 Wiley Periodicals, Inc. congenital eye diseases, reflecting the contributions of these progenitors to multiple cell lineages. Particularly, understanding the underpinnings of neural Key words: neural crest; congenital eye diseases; Axenfeld Rieger syndrome; crest formation will help to discern the complexities of eye development, as congenital glaucoma; eye development these NCCs are involved in every aspect of this process. In this review, we summarize the role of ocular NCCs in eye development, particularly focusing Introduction tal tissues, neurons, and the cranial ganglia (Creuzet Neural crest cells (NCCs) are a population of multipo- et al., 2005; Gage et al., 2005; Kish et al., 2011) (Fig. 1). tent embryonic stem cells that give rise to a wide range With respect to ocular development, the NCCs migrating of cell and tissue types throughout the body. During to the eye are primarily derived from the prosencepha- gastrulation, NCCs originate at the neural plate border lon (developing forebrain) and mesencephalon (devel- and migrate from folds of the neural ectoderm as the oping midbrain) (Whikehart, 2010). These cells give neuroepithelium closes to form the neural tube (Beebe rise to portions of the corneal endothelium and stroma, and Coats, 2000; Creuzet et al., 2005; Whikehart, 2010). iris stroma, ciliary body stroma and muscles, and tra- These cells subsequently migrate, pervading different becular meshwork of the eye (Hay, 1980; Beebe and regions of the embryo and yielding a broad range of tis- Coats, 2000; Cvekl and Tamm, 2004; Gage et al., 2005; sues (from myofiboblasts, melanocytes, endocrine cells, Whikehart, 2010; Kish et al., 2011;). neurons, and glial cells to cartilage and bone) (Beebe While the NCCs are migrating from the edge of the and Coats, 2000; Creuzet et al., 2005; Whikehart, 2010). neural tube, the neuroectodermal-derived optic sulci Both migratory routes and derivatives of neural crest appear as shallow pits along the neural plate and form the vary with rostrocaudal position along the neural tube. optic vesicles that protrude laterally from the prosence- The vagal crest, derived from the caudal hindbrain, con- phalon until apposed to the surface ectodermal-derived tributes to the heart, and together with the sacral neu- optic placode (Creuzet et al., 2005) (Fig. 2). Concomitant ral crest, also form the enteric nervous system that with surface ectoderm thickening for the differentiation of innervates the gut (Creuzet et al., 2005). At the cephalic the lens, morphogenetic movements involving the invagi- level, NCCs form the mesectoderm, which subsequently nation of the optic vesicles leads to formation of a bi- gives rise to craniofacial connective, dermal and skele- layered optic cup (Beebe and Coats, 2000; Creuzet et al., 2005; Harada et al., 2007; Whikehart, 2010; Kish et al., 2011). Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University A loose array of neuroectoderm-derived cranial NCCs, of Michigan termed the periocular mesenchyme (POM), migrate around *Correspondence to: Department of Ophthalmology and Visual Sciences, Kel- the posterior of the optic cup. In humans, the NCC logg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI migrates in three waves, while in mice and chick there 48105. E-mail: [email protected] appears to be only two waves (Johnston et al., 1979; Hay, Published online 4 June 2015 in Wiley Online Library (wileyonlinelibrary.com). 1980; Gage et al., 2005;). In humans, the first wave of Doi: 10.1002/bdrc.21095 NCCs migrates into the space between the anterior surface VC 2015 Wiley Periodicals, Inc. 88 NEURAL CREST DERIVATIVES IN EYE DEVELOPMENT FIGURE 2. Cell migration pattern to the optic cup during eye development. NCCs are indicated in blue and mesodermal cell are indicated in red. Further development of the optic cup involves distinct regionalized differentiation into at least four different structures, including the retina, the retinal pigment epithe- lium (RPE), the iris epithelium, and the ciliary epithelium (Fig. 3). Notably, a second essential function of the POM during ocular development is to provide essential signals FIGURE 1. Migration pathways of NCCs in the developing neural tube. The for the patterning of ocular ectoderm primordia, which migratory routes and derivatives of NCCs vary with rostrocaudal position along not only includes the specification of the RPE from the the neural tube. The vagal crest, derived from the caudal hindbrain, contrib- optic cup, but also the induction of lacrimal glands from utes to the heart, and together with the sacral neural crest, also forms the the surface ectoderm and the differentiation of the optic enteric nervous system that innervates the gut. At the cephalic level, NCCs stalk from the neural ectoderm (Fuhrmann et al., 2000; form the mesectoderm, which subsequently gives rise to craniofacial connec- Gage et al., 2005; Kao et al., 2013). Moreover, cells origi- tive, dermal and skeletal tissues, neurons, and the cranial ganglia. With nating from the surface epithelium interact with the POM respect to ocular development, the NCCs migrating to the eye are primarily for proper eyelid development (Le Lievre and Le Douarin, derived from the prosencephalon (developing forebrain and brainstem) and 1975). mesencephalon (developing midbrain). Over the last decade, studies have highlighted the con- of the lens and the surface ectoderm destined to form the tributions of the NCCs to ocular and periocular develop- corneal epithelium to form the corneal endothelium (Gage ment, emphasizing the importance of these cells in et al., 2005; Whikehart, 2010) (Fig. 3). A second wave of vertebrate ocular evolution. Indeed, defects in neural crest cells migrates between the corneal epithelium and endo- formation lead to severe craniofacial defects and ocular thelium to become the keratinocytes of the corneal stroma. anomalies, and a comprehensive understanding of the inter- The corneal epithelium synthesizes components of the actions involved in the molecular regulation of the neural extracellular matrix for the formation of primary stroma crest would provide insight into the complexities underlying when the lens detaches from the surface ectoderm, while congenital eye diseases. Herein, we discuss the role of ocu- a third wave of NCCs migrates to the angle between the lar NCCs in eye development, particularly focusing on con- posterior cornea (endothelium) and the anterior edge of genital eye diseases associated with anterior segment the optic cup, eventually contributing to the ciliary body defects and the interplay between three prominent mole- and iris stroma (Gage et al., 2005; Whikehart, 2010) (Fig. cules, PITX2, CYP1B1, and retinoic acid (RA), which act in 3). The POM located in the tissues anterior to the chamber concert to specify a population of neural crest-derived mes- angle between the anterior edge of the eye cup and the enchymal progenitors for migration and differentiation to endothelium initially remains undifferentiated at this give rise to distinct anterior segment tissues. We also stage, but subsequently develops into flat endothelial-like describe recent findings suggesting a role for NCCs in ocu- cells, comprising the trabecular meshwork and Schlemm’s lar fissure closure and blood vessel formation and introduce canal, respectively (Gage et al., 2005; Whikehart, 2010) recent evidence suggesting the involvement of NCCs in optic (Fig. 3). fissure closure and vascular angiogenesis. BIRTH DEFECTS RESEARCH (PART C) 105:87–95 (2015) 89 50% of affected individuals (Gage et al., 1999; MacDon- ald et al., 2004; Sowden, 2007; Bohnsack et al., 2011). Molecular genetics studies have identified specific gene mutations, and one of the most commonly affected genes is paired-like homeodomain 2 (PITX2) on chromosome 4q25 (Vaux et al., 1992; Semina et al., 1996, 1997). More than 45 point and chromosomal mutations, including both gain- and loss-of-function of the PITX2 gene, have been identified. ARS
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