The role of sonic hedgehog signaling in the oropharyngeal epithelium during jaw development

Sonic hedgehog (Shh) is expressed in the oropharyngeal epithelium, including the frontonasal ectodermal zone (FEZ), which is defined as the boundary between Shh and Fgf8 expression domains in the frontonasal epithelium. To investigate the role of SHH signaling from the oropharyngeal epithelium, we generated mice in which Shh expression is specifically deleted in the oropharyngeal epithelium (Isl1-Cre; Shh^f/f). In the mutant mouse, Shh expression was excised in the oropharyngeal epithelium as well as FEZ and ventral forebrain, consistent with the expression pattern of Isl1. Isl1-Cre; Shh^f/f mice exhibited a complete loss of lower jaw components and a malformed upper jaw with defects in the cranial base and secondary palate. Massive cell death was observed in the mandibular process at embryonic day (E) 9.5 and E10.5, while mild cell death was observed in the lambdoidal region (the fusion area in the maxillary, lateral nasal, and medial nasal processes) at E10.5. An RNA-seq analysis revealed that Satb2, a gene involved in cell survival during jaw formation, was downregulated in the lambdoidal region in Isl1-Cre; Shh^f/f mice. These results suggest that Shh expression in the FEZ is required for cell survival and skeletogenesis in the lambdoidal region during the development of the upper jaw and that the developmental control governed by SHH signaling is different between upper and lower jaws.