Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9

The initial stages of pancreatic development occur early during mammalian e mbryogenesis(1), but the genes governing this process remain largely unknow n. The homeodomain protein Pdx1 is expressed in the developing pancreatic a nlagen from the approximately 10-somite stage(2,3), and mutations in the ge ne Pdx1 prevent the development of the pancreas(3-5). The initial stages of pancreatic development, however, still occur in Pdx1-deficient mice(3). Hl xb9 (encoding Hb9; ref. 6) is a homeobox gene that in humans has been linke d to dominant inherited sacral agenesis(7) and we show here that Hb9 is exp ressed at early stages of mouse pancreatic development and later in differe ntiated beta-cells. H1xb9 has an essential function in the initial stages o f pancreatic development. In absence of Hlxb9 expression, the dorsal region of the gut epithelium fails to initiate a pancreatic differentiation progr am. In contrast, the ventral pancreatic endoderm develops but exhibits a la ter and more subtle perturbation in beta-cell differentiation and in islet cell organization, Thus, dorsally Hlxb9 is required for specifying the gut epithelium to a pancreatic fate and ventrally for ensuring proper endocrine cell differentiation.