Loss of p130Cas impairs palatal mesenchymal expansion and causes cleft palate

Palatogenesis is a complex developmental process requiring coordinated growth, elevation, and fusion of the palatal shelves. Disruption of these events results in cleft palate, one of the most common congenital craniofacial anomalies. p130Crk-associated substrate (p130Cas) is an adaptor protein involved in integrin-mediated signaling and cytoskeletal regulation; however, its roles in late embryonic development remain poorly understood because global p130Cas-deficiency leads to early embryonic lethality. In this study, we used tamoxifen-inducible conditional knockout mice to investigate the function of p130Cas during 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 by Ki-67 immunostaining and EdU incorporation. Consistently, primary mouse embryonic palatal mesenchymal (MEPM) cells derived from p130Cas-deficient embryos exhibited impaired proliferation and migration in vitro. In contrast, 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. Together, these findings identify p130Cas as an important regulator of palatal mesenchymal expansion during secondary palatogenesis. Impaired proliferative growth of palatal mesenchyme likely underlies the developmental basis of cleft palate in this model.