ISLET1-Dependent β -Catenin/Hedgehog Signaling Is Required for Outgrowth of the Lower Jaw

Abstract

Mandibular patterning information initially resides in the epithelium during development. However, how transcriptional regulation of epithelial-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 to the two growing mandibular elements to be fused surrounding the rostral process of Meckels 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 β-catenin signaling via repression of Wnt antagonists. Re-activation of β-catenin in the epithelium of the Islet1 mutant rescued mandibular morphogenesis through SHH signaling to the mesenchyme. Furthermore, overexpression of transgenic hedgehog ligand in epithelium also partially restored outgrowth of the mandible. These data reveal functional roles for an ISLET1-dependent network integrating β-catenin/SHH signals in mesenchymal cell survival and outgrowth of the mandible during development.