Craniofacial development: genetics, signaling pathways, teratogenic mechanisms, and clinal significance

Abstract Craniofacial development is a highly coordinated and stage-specific process involving neural crest cell migration, proliferation, differentiation, and epithelial-mesenchymal transition. Genetic mutations, signaling pathway abnormalities, and exposure to environmental teratogens can disrupt normal development. These anomalies can lead to cleft palate, craniosynostosis, and other common congenital craniofacial malformations. Although significant progress has been made in understanding craniofacial development in recent years, the systematic integration of these factors remains limited. Here, we provide a comprehensive review of the cellular and molecular mechanisms underlying normal craniofacial development, focusing on the coordinated regulation of cranial neural crest cells by transcription factors, signaling pathways and epigenetic programs. We further summarize major pathogenic mechanisms implicated in craniofacial disorders. Additionally, the teratogenic mechanisms underlying maternal endogenous and external environmental exposures are explored, with particular emphasis on their interactions with genetic factors in reshaping developmental trajectories. We emphasize the central role of gene-environmental interactions in craniofacial pathogenesis by integrating evidence from developmental biology, multi-omics studies and clinical studies. Subsequently, we outline current clinical diagnostic techniques and management strategies for craniofacial malformations, pointing out the existing challenges and future directions. This review establishes a comprehensive framework linking gene regulation, metabolic environment, and clinical implications. It is expected to facilitate deeper insights into disease mechanisms and promoting the translation of basic research findings into clinical diagnosis, prevention, and management of craniofacial disorders.