ISLET1-dependent β-catenin/Hedgehog signaling is required for outgrowth of the lower jaw

Mandibular patterning information initially resides in the epithelium during development. However, how transcriptional regulation of epithelium-derived signaling controls morphogenesis of the mandible remains elusive. Using Shh(Cre) to target the mandibular epithelium, we ablated transcription factor Islet1, resulting in a distally truncated mandible via unbalanced cell apoptosis and decreased cell proliferation in the distal mesenchyme. Loss of Islet1 caused a lack of cartilage at the distal tip, leading the fusion of two growing mandibular elements surrounding the rostral process of Meckel's cartilage. Loss of Islet1 results in dysregulation of mesenchymal genes important for morphogenesis of the mandibular arch. We revealed that Islet1 is required for the activation of epithelial beta-catenin signaling via repression of Wnt antagonists. Reactivation of beta-catenin in the epithelium of the Islet1 mutant rescued mandibular morphogenesis through sonic hedgehog (SHH) signaling to the mesenchyme. Furthermore, overexpression of a transgenic hedgehog ligand in the epithelium also partially restored outgrowth of the mandible. These data reveal functional roles for an ISLET1-dependent network integrating beta-catenin/SHH signals in mesenchymal cell survival and outgrowth of the mandible during development.