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Many craniofacial malformations are linked to cranial neural crest cell (CNCC) dysfunction. This multipotent cell population is essential for craniofacial skeletal development in vertebrates. Their differentiation to cartilage or bone is regulated by key signaling pathways, including Wnt, BMP, FGF, Notch and Hedgehog. These pathways act in concert with broader transcriptional, epigenetic, and tissue-interactions to coordinate craniofacial development. Owing to their external development, genetic tractability and the conservation of fundamental craniofacial developmental mechanisms with humans, the zebrafish are uniquely suited for live imaging, genetic manipulation and investigating the etiology of craniofacial malformations. This review explains how CNCCs give rise to craniofacial skeletal structures during their specification, migration and differentiation. In addition, we discuss how disruption of these processes leads to craniofacial malformations. We emphasize that defects arising at distinct developmental stages are associated with different phenotypic outcomes. In general, early defects in CNCC specification and migration are more often associated with multisystem disorders, including neurocristopathies, hearing loss and cardiac anomalies. Defects in frontonasal CNCC migration more commonly lead to midline and upper facial malformations. By contrast, cartilage and bone malformations can result from defects across multiple stages of CNCC development. We also summarize current zebrafish models and experimental tools, including transgenic reporters, mutant lines, live imaging and single-cell technologies that have advanced our understanding of CNCC biology. Finally, we discuss current limitations and highlight future directions for zebrafish research in the field of craniofacial malformations.
Zhu et al. (Thu,) studied this question.