The role of Rho <scp>GTPases</scp> in facial morphogenesis

Facial morphogenesis relies on the coordinated regulation of cellular behaviors that sculpt the face from simple facial prominences to the fully confluent lip and nose. Disruptions to migration of cranial neural crest cells and/or the directed growth of the prominences will lead to abnormalities such as orofacial clefts. Here we review what is known about the roles of the actin cytoskeleton and its key regulators, the small RHO GTPases, during neural crest cell migration and facial development. Although small RHO GTPase signaling has been studied in the context of cancer and vascular pathologies, their role in facial development has received limited attention. In this review, we review the experimental data that connects changes in the function of small Rho GTPases to cytoskeletal dynamics and ultimately to facial morphogenesis. We also highlight human craniofacial disorders resulting from germline or somatic variants of small Rho GTPase pathway genes as well as associations between variants in GTPase-activating proteins (GAPs) and guanidine nucleotide exchange factors (GEFs) and the complex trait, non-syndromic cleft lip with or without cleft palate. The review points to a model where the gain or loss of RHO GTPase pathway components could be centrally involved in many craniofacial disorders and that the Rho GTPases are major regulators of homeostasis during normal development.