Hedgehog Signaling in Pancreas Epithelium Regulates Embryonic Organ Formation and Adult β-Cell Function

OBJECTIVE: Current studies indicate that Hedgehog (Hh) signaling must be excluded during early stages of pancreas formation. However, conflicting evidence suggests that Hh signaling may be active later during pancreas formation and that it is required for insulin production and secretion in cultured β-cell lines. The objective of this study was to address these discrepancies by assessing the in vivo role of epithelial Hh signaling in the pancreas. RESEARCH DESIGN AND METHODS: To identify Hh-active cells in the developing and adult pancreas epithelium, we characterized transgenic reporter Patched1-LacZ mice. To determine the requirement for epithelial Hh signaling in the pancreas, we eliminated an essential Hh signaling component, Smoothened (Smo), in the pancreatic epithelium, and assessed pancreatic development and adult β-cell physiology phenotypes. RESULTS: Characterization of Patched1-LacZ reporter mice revealed low-level LacZ expression in pancreatic epithelial cells throughout development until birth, when LacZ activity increases in intensity specifically in endocrine and ductal cells. In the absence of Hh signaling, Smo-deficient mice have delayed pancreas formation leading to a temporary reduction in pancreatic epithelium and β-cell numbers. Although β-cell numbers recover by birth, adult Smo-deficient mice display glucose intolerance, increased insulin sensitivity, and reduced total insulin production. CONCLUSIONS: These data show that Hh signaling functions early during pancreas morphogenesis to regulate epithelial and β-cell expansion and to modulate glucose metabolism by regulating insulin production in adult mice.