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

Abstract

The initial stages of pancreatic development occur early during mammalian embryogenesis¹, but the genes governing this process remain largely unknown. The homeodomain protein Pdx1 is expressed in the developing pancreatic anlagen from the approximately 10-somite stage^2,3, and mutations in the gene Pdx1 prevent the development of the pancreas^3,4,5. The initial stages of pancreatic development, however, still occur in Pdx1-deficient mice³. Hlxb9 (encoding Hb9; ref. 6) is a homeobox gene that in humans has been linked to dominant inherited sacral agenesis⁷ and we show here that Hb9 is expressed at early stages of mouse pancreatic development and later in differentiated β-cells. Hlxb9 has an essential function in the initial stages of pancreatic development. In absence of Hlxb9 expression, the dorsal region of the gut epithelium fails to initiate a pancreatic differentiation program. In contrast, the ventral pancreatic endoderm develops but exhibits a later and more subtle perturbation in β-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.