Loss of p130Cas/Bcar1 impairs palatal mesenchymal expansion and causes cleft palate

Palatogenesis is a complex developmental process that requires the coordinated growth, elevation, and fusion of palatal shelves. Disruption of these events results in cleft palate, which is one of the most common congenital, craniofacial anomalies. p130Crk-associated substrate (p130Cas), also known as breast cancer anti-estrogen resistance 1 (BCAR1), is an adaptor protein involved in integrin-mediated signaling and cytoskeletal regulation; however, its role in late embryonic development is poorly understood because global p130Cas-deficiency leads to early embryonic lethality. In the present study, tamoxifen-inducible conditional knockout mice were used to investigate the role of p130Cas in palatal development. Conditional deletion of p130Cas resulted in cleft palate, characterized by impaired horizontal growth of the palatal shelves. Reduced mesenchymal cell proliferation within the palatal shelves was confirmed using Ki-67 immunostaining and EdU incorporation assays. Primary mouse embryonic palatal mesenchymal (MEPM) cells derived from p130Cas-deficient embryos consistently exhibited impaired proliferation and migration in vitro. The epithelial-specific deletion of p130Cas did not result in cleft palate, indicating that p130Cas function in the palatal mesenchyme is critical for normal palatal development. Taken together, these findings indicate that p130Cas is an important regulator of palatal mesenchymal expansion during secondary palatogenesis. The impaired proliferative growth of the palatal mesenchyme likely underlies the developmental basis of cleft palate in this model.