Regulation of pancreas development by hedgehog signaling

Pancreas organogenesis is regulated by the interaction of distinct signalin g pathways that promote or restrict morphogenesis and cell differentiation. Previous work has shown that activin, a TGF beta signaling molecule, permi ts pancreas development by repressing expression of Sonic hedgehog (Shh), a member of the hedgehog :family of signaling molecules that antagonize panc reas development. Here we show that Indian hedgehog (Ihh), another hedgehog family member, and Patched 1 (Ptc1), a receptor and negative regulator of hedgehog activity, are expressed in pancreatic tissue. Targeted inactivatio n of Ihh in mice allows ectopic branching of ventral pancreatic tissue resu lting in an annulus that encircles the duodenum, a phenotype frequently obs erved in humans suffering from a rare disorder known as annular pancreas. S hh(-/-) and Shh(-/-) Ihh(+/-) mutants have a threefold increase in pancreas mass, and a fourfold increase in pancreatic endocrine cell numbers. In con trast, mutations in Ptc1 reduce pancreas gene expression and impair glucose homeostasis, Thus, islet cell, pancreatic mass and pancreatic morphogenesi s are regulated by hedgehog signaling molecules expressed within and adjace nt to the embryonic pancreas. Defects in hedgehog signaling may lead to con genital pancreatic malformations and glucose intolerance.