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Genetics Underlying the Interactions Between Neural Crest Cells and Eye Development

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Genetics Underlying the Interactions Between Neural Crest Cells and Eye Development Journal of Developmental Biology Review Genetics Underlying the Interactions between Neural Crest Cells and Eye Development Jochen Weigele 1,2 and Brenda L. Bohnsack 1,2,* 1 Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago Ave, Chicago, IL 60611, USA; [email protected] 2 Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave, Chicago, IL 60611, USA * Correspondence: [email protected]; Tel.: +1-312-227-6180; Fax: +1-312-227-9411 Received: 16 October 2020; Accepted: 7 November 2020; Published: 10 November 2020 Abstract: The neural crest is a unique, transient stem cell population that is critical for craniofacial and ocular development. Understanding the genetics underlying the steps of neural crest development is essential for gaining insight into the pathogenesis of congenital eye diseases. The neural crest cells play an under-appreciated key role in patterning the neural epithelial-derived optic cup. These interactions between neural crest cells within the periocular mesenchyme and the optic cup, while not well-studied, are critical for optic cup morphogenesis and ocular fissure closure. As a result, microphthalmia and coloboma are common phenotypes in human disease and animal models in which neural crest cell specification and early migration are disrupted. In addition, neural crest cells directly contribute to numerous ocular structures including the cornea, iris, sclera, ciliary body, trabecular meshwork, and aqueous outflow tracts. Defects in later neural crest cell migration and differentiation cause a constellation of well-recognized ocular anterior segment anomalies such as Axenfeld–Rieger Syndrome and Peters Anomaly. This review will focus on the genetics of the neural crest cells within the context of how these complex processes specifically affect overall ocular development and can lead to congenital eye diseases. Keywords: neural crest; optic cup; coloboma; microphthalmia; Axenfeld-Rieger Syndrome; Peters Anomaly 1. Introduction The neural crest is a migratory stem cell population which contributes to numerous structures in the anterior segment of the eye, including the cornea, iris, sclera, ciliary body, trabecular meshwork, and aqueous outflow tracts [1–6]. The importance of this cell population in anterior segment development is highlighted by examples of potentially blinding diseases such as Axenfeld–Rieger syndrome and Peters anomaly (Figure1A,B) that are due to genetic defects in neural crest cell migration and differentiation [7–11]. In addition, animal models have demonstrated that neural crest cells have critical cell non-autonomous effects. Disruption of signaling in neural crest cells can lead to alterations in neural epithelial-derived optic cup formation resulting in microphthalmia, anophthalmia, and coloboma (Figure1C,D) [ 6,12–14]. However, specific interactions between neural crest cells and the neural epithelial-derived optic cup remain undefined. J. Dev. Biol. 2020, 8, 26; doi:10.3390/jdb8040026 www.mdpi.com/journal/jdb J. Dev. Biol. 2020, 8, 26 2 of 24 J. Dev. Biol. 2020, 8, x 2 of 24 Figure 1.1. ClinicalClinical images images of congenitalcongenital ocularocular anomalies.anomalies. ( (AA)) Axenfeld–Rieger Axenfeld–Rieger syndrome is characterized by by Rieger Rieger Anomaly Anomaly (iris (iris hypoplasia hypoplasia resulting resulting in pseudopolycoria in pseudopolycoria and corectopia and corectopia (white (whitearrowheads)) arrowheads)) and Axenfeld and Axenfeld Anomaly Anomaly (anteriorization (anteriorization of Schwalbe’s of Schwalbe’s line line of ofthe the cornea cornea (posterior (posterior embryotoxon, black arrows) with iris adhesions). These defects ar aree due to abnormal migration and differentiationdifferentiation of of neural neural crest crest cells cells into into the the anterior anterior segment segment of the ofthe eye. eye. Over Over 50% 50%of individuals of individuals with withAxenfeld–Rieger Axenfeld–Rieger syndrome syndrome develop develop glaucoma glaucoma which which often oftenrequires requires surgery surgery such suchas placement as placement of a glaucomaof a glaucoma drainage drainage device device (asterisk). (asterisk). (B) In Peters (B) In anomaly, Peters anomaly, there is there a circumscribed is a circumscribed central corneal central opacificationcorneal opacification (outlined (outlined by dotted by white dotted line) white with line) iris-corneal with iris-corneal adhesions adhesions (black arrowhead). (black arrowhead). These Theseanomalies anomalies are due are to due abnormal to abnormal separation separation of the of le thens lensvesicle vesicle from from the thesurfac surfacee ectoderm ectoderm resulting resulting in absencein absence of ofDescemet’s Descemet’s membrane membrane and and disruption disruption of of neural neural crest crest cell cell migration migration into into the anterior segment. ( (CC), Dand) Colobomas (D) Colobomas are due are todue incomplete to incomplete closure closure of the of ocular the ocular fissure fissure and and can acanffect affect the iris,the iris,zonules, zonules, retina, retina, choroid, choroid, and opticand optic nerve. nerve. Chorioretinal Chorioretinal colobomas colobomas are inferiorare inferior to the to opticthe optic nerve nerve and andare characterizedare characterized by anby areaan area that that isdevoid is devoid of of retina retina and and choroid choroid (C (,C white, white arrows). arrows). InIn thesethese types of coloboma, the macula ((+)+) which accounts for central vision, is typically not aaffected.ffected. Optic nerve colobomas (D, white arrows) can cause severe vision loss especially if the entire optic nerve (outlined by black dotted line) is involved. Although the maculamacula ((+)+) may may not not be be affected, affected, the loss of the ganglion cell axons that comprise the optic nerve limits vision.vision. Neural crest development is a complex process, which is characterized by several landmark events [15–17]. [15–17]. Immediately Immediately after gastrulation, the ectodermal germ layer is subdivided and specified specified through didifferentfferent extracellular signaling systemssystems intointo twotwo territories: the non-neural ectoderm which gives rise to the epidermis and the neural ectoderm, which forms forms the the central central nervous nervous system system [17–20]. [17–20]. These territories are separated by the neural plate border, from which neural crest cells are specifiedspecified during neural tube closure (Figure(Figure2 2))[ [17,20,21].17,20,21]. Unique among stem cell populations, neural crest cells then undergo epithelial-to-mesenchymal transition (EMT), delaminate from the neural tube (Figure3 3),), andand migratemigrate toto didifferentfferent regions of the embryoembryo to give rise to a broad range of tissues and cells (Figures 44 and and5 )[5) [2,22,23].2,22,23]. Each of these su successiveccessive processes, neural plate border induction, neural crest specification,specification, neural crest mi migration,gration, and neural crest differentiation differentiation is controlled by overlapping gene regulatory networks [[15,17,24].15,17,24]. J. Dev. Biol. 2020, 8, 26 3 of 24 J. Dev. Biol. 2020, 8, x 3 of 24 J. Dev. Biol. 2020, 8, x 3 of 24 Figure 2. Neural plate border induction. In neural plate border induction, FGF followed by Notch and FigureFigure 2. Neural 2. Neural plate plate border border induction. induction. In In neural neural plate plate border border induction, FGF FGF followed followed by byNotch Notch and and BMP signaling are expressed in the neural ectoderm while Wnt is expressed in the non-neural BMP signalingBMP signaling are expressed are expressed in the neuralin the ectodermneural ectode whilerm Wntwhile is Wnt expressed is expressed in the non-neuralin the non-neural ectoderm. ectoderm. In the next phases of neurulation and optic groove formation, these signals then induce In the nextectoderm. phases In ofthe neurulation next phases andof neurulation optic groove and formation, optic groove these formation, signals th thenese signals induce then expression induce of expressionexpression of of the the neural neural plate plate border border specifiers, specifiers, Msx1/2, Msx1/2, Zic2, Zic2, and and Tfap2. Tfap2. These These transcription transcription factors, factors, the neural plate border specifiers, Msx1/2, Zic2, and Tfap2. These transcription factors, expressed within expressedexpressed withinwithin thethe neuralneural plateplate border,border, triggetrigger r signalingsignaling cascadescascades thatthat maintainmaintain stemstem cellcell the neural plate border, trigger signaling cascades that maintain stem cell pluripotency and prepare the pluripotencypluripotency and and prepare prepare the the prem premigratoryigratory neural neural crest crest cells cells for for epithelial-mesenchymal epithelial-mesenchymal transition transition premigratory(EMT).(EMT). neural crest cells for epithelial-mesenchymal transition (EMT). Figure 3. Neural crest cell specification. As the neural tube closes, genes including Sox10, Foxd3, Alx1, FigureFigure 3. 3. Neural Neural crest crest cell cell specification. specification. As As the the neural neural tube tube closes, closes, genes genes including including Sox10, Sox10, Foxd3, Foxd3, Alx1, Alx1, Tfap2a,Tfap2a,Tfap2a,Tcof, Tcof,Nlz1 Tcof, Nlz1// 2Nlz1/, and2,2, and Snai1and Snai1/2 Snai1/2/2 induce induce induce neural neural neural crest crest crest cellcell cell identity identity identity
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