Transcriptional factor <scp>ISL</scp> 1 regulates palate development by tuning the <scp>SHH</scp> cascade

Cleft palate is one of the most common birth defects in humans, and palate morphogenesis depends on epithelial-mesenchymal interaction. In this study, we report that ablation of Isl1 in the epithelium leads to complete cleft palate. A significant reduction in mesenchymal cell proliferation was detected in the Isl1^Pitx2Cre mutant palates, but there was no significant difference in apoptosis between wild-type and mutant embryos. Fewer rugae structures were observed in Isl1^Pitx2Cre mutant embryos. Shh, Sox2, Foxe1, Foxd2, and Msx1 expression was downregulated in the developing palate in Isl1 mutant embryos. We found that ISL1 can directly regulate Shh expression in palatal epithelial cells, suggesting a critical role for ISL1 in epithelial-mesenchymal interactions during palate development. Remarkably, cleft palate defects due to Isl1 deletion were rescued by a conditional transgenic allele (Tg-pmes-Ihh), confirming the genetic integration of Hedgehog signaling. Our findings indicate that ISL1 controls palatal shelf morphogenesis by modulating epithelial-mesenchymal communication via SHH signaling.