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Each year approximately 35% of babies are born with craniofacial abnormalities of the skull, jaws, ears, and/or teeth, which in turn can lead to problems in feeding, hearing, and sight [...]
Citation: Tavares, A.L.P.; Moody, S.A.
Advances in Understanding the
Pathogenesis of Craniofacial Birth
Defects. J. Dev. Biol. 2022,10, 27.
Received: 9 June 2022
Accepted: 15 June 2022
Published: 1 July 2022
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Journal of
Advances in Understanding the Pathogenesis of Craniofacial
Birth Defects
Andre L. P. Tavares and Sally A. Moody *
Department of Anatomy & Cell Biology, George Washington University School of Medicine and Health Sciences,
Washington, DC 20052, USA;
*Correspondence:; Tel.: +1-202-994-2878
Each year approximately 35% of babies are born with craniofacial abnormalities of
the skull, jaws, ears, and/or teeth, which in turn can lead to problems in feeding, hearing,
and sight. Because of this high incidence and the clinical importance of correcting skele-
tal dysmorphologies by surgical interventions, the developmental biology and pediatric
research communities have been highly engaged in investigating how these tissues form
during normal development and discovering the genetic underpinnings of the hundreds of
distinct congenital craniofacial syndromes. A large body of previous research has eluci-
dated many of the cellular and molecular processes that underlie the normal interactions
between the various embryonic cell types that contribute to these tissues as well as the
genes and signals that are aberrant in craniofacial syndromes. In recent years, however,
research has focused on using advanced genomic and transcriptomic approaches to screen
patients for causative variants, high resolution imaging, and morphometrics to describe
phenotypes more accurately, and animal models that harbor human syndromic variants.
Many of these advances are exemplified in the studies that comprise this Special Issue on
“Craniofacial Genetics and Developmental Biology”, revealing many new insights into
normal and aberrant craniofacial development.
One of the major embryonic contributors to the craniofacial tissues is the cranial
neural crest, a pluripotent population of cells originating from the border of the neural
plate that migrate away from the neural tube as it closes and migrate into the periphery
to form multiple craniofacial tissues, including the anterior skull and the skeleton of
the face. In this Special Issue, Siismets and Hatch [
] review our current understanding
of the contribution of neural crest to craniofacial development and various craniofacial
anomalies, and then focus on the pathogenesis of coronal craniosynostosis, the premature
closure of the coronal suture that causes significant clinical outcomes. The authors also
discuss potential approaches for craniofacial tissue regeneration as well as treatment for
craniosynostosis. Weigele and Bohnsack’s review [
] focuses on the key role that the cranial
neural crest plays during ocular development and congenital eye diseases. Neural crest
interactions with the periocular mesenchyme and the neural tube-derived optic cup are
critical for ocular morphogenesis; defects in these interactions result in microphthalmia
and coloboma. Cranial neural crest cells also contribute to the cornea, iris, sclera, ciliary
body, trabecular meshwork, and aqueous outflow tracts; defects in their migration and
differentiation can cause numerous anomalies in these ocular structures, such as Axenfeld-
Reiger Syndroma and Peters Anomaly. Another study in this Special Issue used the
forward-genetics approach of ENU mutagenesis in mouse to identify a new player in ocular
development [
]; Blizzard et al. discovered a new, hypomorphic allele of Cse1l, whose
wildtype protein functions in several cellular processes including nuclear transport, cell
cycle, and apoptosis. The previously reported Cse1l-null mutant is early embryonic lethal,
whereas the hypomorphic Cse1l mutants described in this report survive to organogenesis
stages, presenting with a number of variable craniofacial and ocular phenotypes including
microphthalmia and coloboma. While embryonic Cse1l expression is widespread, it is
J. Dev. Biol. 2022,10, 27.
J. Dev. Biol. 2022,10, 27 2 of 4
highly expressed in the migrating cranial neural crest, consistent with the affected tissues.
The authors suggest that this new allele provides evidence that CSE1L should be considered
in patients with eye and craniofacial abnormalities of unknown cause.
Defects in components of the cranial skeleton are a hallmark of a number of craniofacial
syndromes. Many syndromes include dysmorphologies of the cranial vault, called the
calvarium. The anterior portion of the calvarium is derived from the cranial neural crest,
whereas the posterior portion derives from paraxial mesoderm. In this Special Issue,
Parmar et al. [
] studied the role of cyclooxygenase-2 (Cox2) in calvarial development; Cox2
catalyzes the formation of prostaglandin E2 (PGE2) which is required for cell proliferation,
migration, epithelial-mesenchymal transition, and differentiation in a variety of tissues.
They found that loss of Cox2 leads to abnormal calvarial development. Reducing Cox2
activity reduced the level of PGE2, which in turn led to reduced expression of cell adhesion
molecules (E- and N-cadherins) and their regulators (Msx1, Tgf-beta) that are necessary
for normal migration of the neural crest into the calvarial primordium. In another study
of calvarial development, Ibarra et al. [
] experimentally demonstrated that coordination
between Wnt/beta-Catenin and Erk signaling regulates the adoption of cartilage versus
bone fate in the neural crest-derived cranial mesenchyme that forms the calvarium. Loss
of Erk signaling led to ectopic cartilage in the frontal bone primordium indicating a shift
from osteogenic fate to chondrogenic fate. These two studies significantly contribute to our
understanding of the molecular control of calvarial development.
Another prominent class of dysmorphologies are those that affect the midface, jaws,
and teeth. Liberton et al. [
] tested whether dentofacial deformities known as skeletal
malocclusions contribute to the craniofacial morphology of non-syndromic cleft lip and
palate patients. By comparing the geometric morphometry data obtained by advanced
imaging—full skull cone beam computed tomography—of sex- and ethnicity-matched
patients, these authors found that both the cleft and the malocclusion contribute to the
extent of the craniofacial phenotype. Dasgupta et al. [
] report that R-spondins, secreted
proteins that augment Wnt signaling, are required for the formation of lower jaw incisors.
Using compound mutant mice, they showed that simultaneous deletion of two members of
the R-spondin family led to hypoplasia of the mandible and cleft secondary palate as well
as severe dental abnormalities. This paper is the first evidence that R-spondin signaling
promotes the normal process of odontogenesis in mammals. Ko et al. [
] investigated the
mechanism by which teeth and jaws fit, function, and evolve together. They tested whether
molar teeth only begin to grow once the jaw develops enough space from the previously
erupted tooth. Using another advanced imaging technique—synchrotron-based micro-CT
scanning—they assessed developing molars in the mouse jaw from E10 to P32. They found
that conditions within the dental lamina itself, rather than jaw growth, have the greater
influence on molar spacing. Their data support the conclusion that molar initiation is
contingent on sufficient surface area for the dental epithelium to reorganize and invaginate
into the underlying mesenchyme.
The cranial base, which is derived from both neural crest (anterior elements) and
paraxial mesoderm (posterior elements), has been less studied than the calvarium and
jaws. However, recent work shows that defects in its development can have widespread
craniofacial consequences. In the review by Venugopalan and Van Otterloo [
], the authors
focus on the signals and genes that regulate the development of the cranial base in animal
models and humans. Unlike the skeletal elements of the calvarium and face, which
develop by intramembranous ossification, the cranial base skeleton develops from an
intermediate chondrocranium similar to the long bones of the trunk. These authors compare
the gene regulatory networks that may differ between these two modes of bone formation
and pose many questions regarding their roles in evolutionary diversity of shape and
congenital dysmorphologies. Because craniofacial birth defects often include anomalies of
the cranial base, it is important to elucidate the developmental regulation of this region
of the skeleton. In support of this conclusion, Kidwai et al. [
] present a case report
of Muenke syndrome (MS), a disease caused by the p.Pro250Arg variant in FGFR3 and
J. Dev. Biol. 2022,10, 27 3 of 4
characterized by coronal suture synostosis, macrocephaly, dysmorphic craniofacial features,
and dental malocclusion. However, because phenotypes are highly variable and penetrance
is incomplete, it is difficult to unravel the cellular and molecular mechanisms underlying
MS. To establish a rigorous phenotypic framework to account for skeletal phenotypic
variance, the authors quantitatively delineated the craniofacial phenotype of an individual
with MS and compared this to his unaffected parents using 3-dimensional cephalometric
analysis of cone beam computed tomography scans and geometric morphometric analysis.
The measurements of the proband illustrated a shortened anterior and middle cranial
base. Interestingly, while measurements of both unaffected parents were within the normal
clinical range, they were at variance with a separate, healthy control dataset, suggesting
while they do not carry the mutation, they may carry modifiers that contribute to the
phenotype. These results suggest that clinically unremarkable, but shortened cranial base
bones likely have downstream effects on the other craniofacial phenotypes. This study
highlights how deep morphological assessment in both affected and unaffected family
members can lead to more focused research questions and examine the impact of genetic
variants on craniofacial development.
This Special Issue also presents work that addresses the function of variants found
by GWAS and next-generation sequencing to be causative in a few human craniofacial
syndromes. Motch Perrine et al. [
] review the current understanding of the highly
variable phenotypes associated with Pierre Robin syndrome. Basing their study on these
phenotypes, which include small jaws, tongue displacement, and cleft palate, and on
our knowledge of how the affected tissues develop, the authors provide a list of genes
whose misregulation may contribute to Pierre Robin syndrome. They also provide a list
of the available animal models that could be used to better understand the genetic basis
and phenotype variation in this syndrome. In the MS case report cited above [
], the
authors generated iPSCs from each member of the family trio to try to understand how the
p.Pro250Arg variant of the proband affects the function of FGFR3. The structural changes
in the MS receptor are predicted to confer greater promiscuity for atypical ligands. Using
a novel imaging approach—two-photon fluorescence lifetime imaging microscopy—the
autofluorescence decay of specific amino acids data collected from the iPSC cells supported
this prediction by showing a shorter half-life for the MS FGFR3 compared to the wild-type
FGFR3 from either parent. The authors posit that these cell lines will serve as a reliable,
patient-specific platform with which to understand the cellular processes that are affected in
MS. The variants associated with another craniofacial syndrome, Branchio-Oto-Renal (BOR)
syndrome, were investigated by Mehdizadeh et al. [
]. They expressed the homologues of
four different human variants of SIX1 (BOR) in wild-type Xenopus embryos to model this
autosomal dominant disease in which patients express one wild-type allele and one mutant
allele. Previous work from this laboratory demonstrated that variants of either the cofactor-
binding domain or the DNA-binding domain each altered—in unique combinations—gene
expression in both the neural crest and sensory placodes at neural plate stages. In this
study, they focused on how these variants affect gene expression in the primordium of the
inner ear—the otic vesicle. The four different single nucleotide variants, each of which
has defective transcriptional activity, showed different effects on a suite of otic genes. The
authors propose that these differences arise from differences in the ability of cofactors to
bind to each variant, which then differentially interfere with their ability to drive otic gene
expression, which ultimately may contribute to patient phenotype variability.
This exciting collection of articles that address fundamental issues in normal and
aberrant craniofacial development demonstrates the unexpected new information that can
be obtained by using new methodologies and several different appropriate animal models.
Relating the fundamental information to the clinical literature and case reports promises to
advance treatment for these all-too-frequent syndromes.
J. Dev. Biol. 2022,10, 27 4 of 4
Conflicts of Interest:
Tavares and Moody are coauthors of one of the publications included in the
special issue [
]. The funders had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Siismets, E.M.; Hatch, N.E. Cranial neural crest cells and their role in the pathogenesis of craniofacial anomalies and coronal
craniosynostosis. J. Dev. Biol. 2020,8, 18. [CrossRef] [PubMed]
Weigele, J.; Bohnsack, B.L. Genetics underlying the interaction between neural crest cells and eye development. J. Dev. Biol.
8, 26. [CrossRef] [PubMed]
Blizzard, L.E.; Menke, C.; Patel, S.D.; Waclaw, R.R.; Lachke, S.A.; Stottmann, R.W. A Novel Mutation in Cse1l Disrupts Brain and
Eye Development with Specific Effects on Pax6 Expression. J. Dev. Biol. 2021,9, 27. [CrossRef] [PubMed]
Parmar, B.; Verma, U.; Khaire, K.; Danes, D.; Balakrishnan, S. Inhibition of Cyclooxygenase-2 Alters Craniofacial Patterning
during Early Embryonic Development of Chick. J. Dev. Biol. 2021,9, 16. [CrossRef] [PubMed]
Ibarra, B.A.; Machen, C.; Atit, R.P. Wnt-dependent activation of ERK mediates repression of chondrocyte fate during calvarial
development. J. Dev. Biol. 2021,9, 23. [CrossRef]
Liberton, D.K.; Varma, P.; Almpani, K.; Fing, P.W.; Mishra, R.; Oberoi, S.; Senel, F.C.; Mah, J.K.; Huang, J.; Padwa, B.L.; et al.
Craniofacial analysis may indicate co-occurrence of skeletal malocclusions and associated risks in development of cleft lip and
palate. J. Dev. Biol. 2020,8, 2. [CrossRef]
Dasgupta, K.; Cesario, J.M.; Ha, S.; Asam, K.; Deacon, L.J.; Song, A.H.; Kim, J.; Cobb, J.; Yoon, J.K.; Jeong, J. R-Spondin 3 regulates
mammalian dental and craniofacial development. J. Dev. Biol. 2021,9, 31. [CrossRef] [PubMed]
Ko, D.; Kelly, T.; Thompson, L.; Uppal, J.K.; Rostampous, N.; Webb, M.A.; Zhu, N.; Belex, G.; Mondal, P.; Cooper, D.M.L.; et al.
Timing of mouse molar formation is independent of jaw length including retromolar space. J. Dev. Biol.
,9, 8. [CrossRef]
9. Venugopalan, S.R.; Van Otterloo, E. The skull’s girder: A brief review of the cranial base. J. Dev. Biol. 2021,9, 3.
Kidwai, F.K.; Mui, B.W.H.; Almpani, K.; Jani, P.; Keyvanfar, C.; Iqbal, K.; Paravastu, S.S.; Arora, D.; Orzechowski, P.;
Merling, R.K.; et al.
Quantitative craniofacial analysis and generation of human induced pluripotent stem cells for Muenke
Syndrome: A case report. J. Dev. Biol. 2021,9, 39. [CrossRef] [PubMed]
Motch Perrine, S.M.; Wu, M.; Holmes, G.; Bjork, B.C.; Wang Jabs, E.; Richtsmeier, J.T. Phenotypes, developmental basis, and
genetics of Pierre Robin complex. J. Dev. Biol. 2020,8, 30. [CrossRef] [PubMed]
Mehdizadeh, T.; Majumdar, H.D.; Ahsan, S.; Tavares, A.L.P.; Moody, S.A. Mutations in SIX1 associated with Branchio-oto-renal
syndrome (BOR) differentially affect otic expression of putative target genes. J. Dev. Biol. 2021,9, 25. [CrossRef] [PubMed]
ResearchGate has not been able to resolve any citations for this publication.
Full-text available
In this case report, we focus on Muenke syndrome (MS), a disease caused by the p.Pro250Arg variant in fibroblast growth factor receptor 3 (FGFR3) and characterized by uni- or bilateral coronal suture synostosis, macrocephaly without craniosynostosis, dysmorphic craniofacial features, and dental malocclusion. The clinical findings of MS are further complicated by variable expression of phenotypic traits and incomplete penetrance. As such, unraveling the mechanisms behind MS will require a comprehensive and systematic way of phenotyping patients to precisely identify the impact of the mutation variant on craniofacial development. To establish this framework, we quantitatively delineated the craniofacial phenotype of an individual with MS and compared this to his unaffected parents using three-dimensional cephalometric analysis of cone beam computed tomography scans and geometric morphometric analysis, in addition to an extensive clinical evaluation. Secondly, given the utility of human induced pluripotent stem cells (hiPSCs) as a patient-specific investigative tool, we also generated the first hiPSCs derived from a family trio, the proband and his unaffected parents as controls, with detailed characterization of all cell lines. This report provides a starting point for evaluating the mechanistic underpinning of the craniofacial development in MS with the goal of linking specific clinical manifestations to molecular insights gained from hiPSC-based disease modeling.
Full-text available
Development of the teeth requires complex signaling interactions between the mesenchyme and the epithelium mediated by multiple pathways. For example, canonical WNT signaling is essential to many aspects of odontogenesis, and inhibiting this pathway blocks tooth development at an early stage. R-spondins (RSPOs) are secreted proteins, and they mostly augment WNT signaling. Although RSPOs have been shown to play important roles in the development of many organs, their role in tooth development is unclear. A previous study reported that mutating Rspo2 in mice led to supernumerary lower molars, while teeth forming at the normal positions showed no significant anomalies. Because multiple Rspo genes are expressed in the orofacial region, it is possible that the relatively mild phenotype of Rspo2 mutants is due to functional compensation by other RSPO proteins. We found that inactivating Rspo3 in the craniofacial mesenchyme caused the loss of lower incisors, which did not progress beyond the bud stage. A simultaneous deletion of Rspo2 and Rspo3 caused severe disruption of craniofacial development from early stages, which was accompanied with impaired development of all teeth. Together, these results indicate that Rspo3 is an important regulator of mammalian dental and craniofacial development.
Full-text available
Forward genetics in the mouse continues to be a useful and unbiased approach to identifying new genes and alleles with previously unappreciated roles in mammalian development and disease. Here, we report a new mouse allele of Cse1l that was recovered from an ENU mutagenesis screen. Embryos homozygous for the anteater allele of Cse1l display a number of variable phenotypes, with craniofacial and ocular malformations being the most obvious. We provide evidence that Cse1l is the causal gene through complementation with a novel null allele of Cse1l generated by CRISPR-Cas9 editing. While the variability in the anteater phenotype was high enough to preclude a detailed molecular analysis, we demonstrate a very penetrant reduction in Pax6 levels in the developing eye along with significant ocular developmental phenotypes. The eye gene discovery tool iSyTE shows Cse1l to be significantly expressed in the lens from early eye development stages in embryos through adulthood. Cse1l has not previously been shown to be required for organogenesis as homozygosity for a null allele results in very early lethality. Future detailed studies of Cse1l function in craniofacial and neural development will be best served with a conditional allele to circumvent the variable phenotypes we report here. We suggest that human next-generation (whole genome or exome) sequencing studies yielding variants of unknown significance in CSE1L could consider these findings as part of variant analysis.
Full-text available
Several single-nucleotide mutations in SIX1 underlie branchio-otic/branchio-oto-renal (BOR) syndrome, but the clinical literature has not been able to correlate different variants with specific phenotypes. We previously assessed whether variants in either the cofactor binding domain (V17E, R110W) or the DNA binding domain (W122R, Y129C) might differentially affect early embryonic gene expression, and found that each variant had a different combination of effects on neural crest and placode gene expression. Since the otic vesicle gives rise to the inner ear, which is consistently affected in BOR, herein we focused on whether the variants differentially affected the otic expression of genes previously found to be likely Six1 targets. We found that V17E, which does not bind Eya cofactors, was as effective as wild-type Six1 in reducing most otic target genes, whereas R110W, W122R and Y129C, which bind Eya, were significantly less effective. Notably, V17E reduced the otic expression of prdm1, whereas R110W, W122R and Y129C expanded it. Since each mutant has defective transcriptional activity but differs in their ability to interact with Eya cofactors, we propose that altered cofactor interactions at the mutated sites differentially interfere with their ability to drive otic gene expression, and these differences may contribute to patient phenotype variability.
Full-text available
Wnt signaling regulates cell fate decisions in diverse contexts during development, and loss of Wnt signaling in the cranial mesenchyme results in a robust and binary cell fate switch from cranial bone to ectopic cartilage. The Extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and Wnt signaling pathways are activated during calvarial osteoblast cell fate selection. Here, we test the hypothesis that ERK signaling is a mediator of Wnt-dependent cell fate decisions in the cranial mesenchyme. First, we show that loss of Erk1/2 in the cranial mesenchyme results in a diminished domain of osteoblast marker expression and increased expression of cartilage fate markers and ectopic cartilage formation in the frontal bone primordia. Second, we show that mesenchyme Wnt/β-catenin signaling and Wntless are required for ERK activation in calvarial osteoblasts. Third, we demonstrate that Wnt and ERK signaling pathways function together to repress SOX9 expression in mouse cranial mesenchyme. Our results demonstrate an interaction between the Wnt and ERK signaling pathways in regulating lineage selection in a subset of calvarial cells and provide new insights into Wnt-dependent cell fate decisions.
Full-text available
A recent study from our lab revealed that the inhibition of cyclooxygenase-2 (COX-2) exclusively reduces the level of PGE2 (Prostaglandin E2) among prostanoids and hampers the normal development of several structures, strikingly the cranial vault, in chick embryos. In order to unearth the mechanism behind the deviant development of cranial features, the expression pattern of various factors that are known to influence cranial neural crest cell (CNCC) migration was checked in chick embryos after inhibiting COX-2 activity using etoricoxib. The compromised level of cell adhesion molecules and their upstream regulators, namely CDH1 (E-cadherin), CDH2 (N-cadherin), MSX1 (Msh homeobox 1), and TGF-β (Transforming growth factor beta), observed in the etoricoxib-treated embryos indicate that COX-2, through its downstream effector PGE2, regulates the expression of these factors perhaps to aid the migration of CNCCs. The histological features and levels of FoxD3 (Forkhead box D3), as well as PCNA (Proliferating cell nuclear antigen), further consolidate the role of COX-2 in the migration and survival of CNCCs in developing embryos. The results of the current study indicate that COX-2 plays a pivotal role in orchestrating craniofacial structures perhaps by modulating CNCC proliferation and migration during the embryonic development of chicks.
Full-text available
For humans and other mammals to eat effectively, teeth must develop properly inside the jaw. Deciphering craniodental integration is central to explaining the timely formation of permanent molars, including third molars which are often impacted in humans, and to clarifying how teeth and jaws fit, function and evolve together. A factor long-posited to influence molar onset time is the jaw space available for each molar organ to form within. Here, we tested whether each successive molar initiates only after a minimum threshold of space is created via jaw growth. We used synchrotron-based micro-CT scanning to assess developing molars in situ within jaws of C57BL/6J mice aged E10 to P32, encompassing molar onset to emergence. We compared total jaw, retromolar and molar lengths, and molar onset times, between upper and lower jaws. Initiation time and developmental duration were comparable between molar upper and lower counterparts despite shorter, slower-growing retromolar space in the upper jaw, and despite size differences between upper and lower molars. Timing of molar formation appears unmoved by jaw length including space. Conditions within the dental lamina likely influence molar onset much more than surrounding jaw tissues. We theorize that molar initiation is contingent on sufficient surface area for the physical reorganization of dental epithelium and its invagination of underlying mesenchyme.
Full-text available
The cranial base is a multifunctional bony platform within the core of the cranium, spanning rostral to caudal ends. This structure provides support for the brain and skull vault above, serves as a link between the head and the vertebral column below, and seamlessly integrates with the facial skeleton at its rostral end. Unique from the majority of the cranial skeleton, the cranial base develops from a cartilage intermediate—the chondrocranium—through the process of endochondral ossification. Owing to the intimate association of the cranial base with nearly all aspects of the head, congenital birth defects impacting these structures often coincide with anomalies of the cranial base. Despite this critical importance, studies investigating the genetic control of cranial base development and associated disorders lags in comparison to other craniofacial structures. Here, we highlight and review developmental and genetic aspects of the cranial base, including its transition from cartilage to bone, dual embryological origins, and vignettes of transcription factors controlling its formation.
Full-text available
The phenotype currently accepted as Pierre Robin syndrome/sequence/anomalad/complex (PR) is characterized by mandibular dysmorphology, glossoptosis, respiratory obstruction, and in some cases, cleft palate. A causative sequence of developmental events is hypothesized for PR, but few clear causal relationships between discovered genetic variants, dysregulated gene expression, precise cellular processes, pathogenesis, and PR-associated anomalies are documented. This review presents the current understanding of PR phenotypes, the proposed pathogenetic processes underlying them, select genes associated with PR, and available animal models that could be used to better understand the genetic basis and phenotypic variation of PR.
Full-text available
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