Role of Hedgehog Signaling on the differentiation of pancreas and pancreatic beta-cell function

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Aim/hypothesis. Ectopic activation of hedgehog (Hh) signaling in pancreas induces various abnormal morphogenetic events in the pancreas. This study analyzed the dose-dependent requirement of Patched (Ptc)1, a negative regulator of Hh signaling on pancreatic development.Methods. A recessive spontaneous mutant mouse, mesenchymal dysplasia (mes) express a mutated Ptcl, resulting in deletion of the most carboxy-terminal cytoplasmic domain of the Ptcl protein. In this study, we analyzed pancreatic morphology in Ptc1^+/+, Ptc1^+/mes, Ptc1^mes/mes., and Ptc1^/mes mouse embryos, as well as the islet mass in adult Ptc1^+/+, Ptc1^+/mes, and Ptc1^+1- mice.Results. Until embryonic day (E) 12.5, no obvious abnormality of pancreas was observed in each Ptc1 mutant. The expression patterns of Pdx1, glucagon, insulin were also not evidently different among the mice genotypes studied. Thereafter, morphological abnormalities appeared in the Ptcl mutant mice. The beta-, alpha-, and exocrine-cell masses decreased at E18.5 in parallel with increased Hh signaling. Among these, the beta cell mass showed the highest sensitively to Hh signaling with a significant decrease even in Ptc1^+1mes, mice. Adult Ptc1^+1- mice also showed a significant decrease in beta cell mass compared to wild-type mice.Conclusions/interpretation. Our findings indicate that the carboxy-terminal domain of Ptc1 is essential for pancreatic development. In addition, the loss of Ptc1 function decreases both the endocrine and exocrine cell mass in a dose-dependent manner, with beta cells particularly sensitive to changes in Hh signaling.