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Loss of p130Cas impairs palatal mesenchymal expansion and causes cleft palate

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE326799 | GEO | 2026/04/07

REPOSITORIES: GEO

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			Action	DRS
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	GSE326799_E14_palate_FPKM_matrix.txt.gz	Txt

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Project description:We identify a role for two evolutionarily related, secreted metalloproteases of the ADAMTS family (A disintegrin-like and metalloprotease domain with thrombospondin type-1 motif), ADAMTS20 and ADAMTS9, in palatogenesis. Adamts20 mutations cause the mouse white spotting mutant belted (bt), whereas Adamts9 is essential for survival beyond 7.5 days of gestation (E7.5). Functional overlap of Adamts9 with Adamts20 was established in bt/bt:Adamts9+/- mice, which have increased white spotting relative to bt mice, as previously reported, and a fully penetrant cleft palate. Palatal closure was delayed, although eventually completed, in both bt/+;Adamts9+/- and bt/bt mice, demonstrating a cooperative role of these related genes. Adamts9 and Adamts20 are both expressed in palatal mesenchyme, with Adamts9 expressed exclusively in microvascular endothelial cells. Palatal shelves from bt/bt:Adamts9+/- mice fused in culture, suggesting an intact TGF signaling pathway in palatal epithelium, and indicating a temporally specific delay in palatal shelf elevation and growth toward the midline. Palatal shelf mesenchymal cells showed a statistically significant decrease of cell proliferation at E13.5 and E14.5, as well as decreased processing of versican, an ADAMTS substrate, at these stages. Vcan haploinsufficiency led to a greater penetrance of cleft palate in bt mice, and impaired proliferation was also seen in palatal mesenchymal cells of these mice, suggesting a role for ADAMTS-mediated versican proteolysis in palatal closure. In a parallel with recent work identifying a role for a bioactive ADAMTS-generated versican fragment in regulating apoptosis during interdigital web regression, we propose that versican proteolysis may influence palatal mesenchymal cell proliferation. Palatal shelves were dissected from four E13.75 Adamts9+/-:bt/bt embyos (correspond to the 4 samples: Palate_Adamts9+/-:bt/bt_Rep1, Palate_Adamts9+/-:bt/bt_Rep2, Palate_Adamts9+/-:bt/bt_Rep3 and Palate_Adamts9+/-:bt/bt_Rep4) and age-matched 3 wild-type C57Bl/6 embryos (correspond to the 3 samples: Palate_WT_Rep1, Palate_WT_Rep2, and Palate_WT_Rep3) that were used as the controls

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Loss of p130Cas impairs palatal mesenchymal expansion and causes cleft palate

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