[Abstract unavailable

The functional unit of the endocrine pancreas is the islet of Langerhans. Islets are nested within the exocrine tissue of the pancreas and are composed of alpha-, beta-, delta- and gamma-cells. beta-Cells produce insulin and form the core of the islet, whereas alpha-, delta- and gamma-cells are arranged at the periphery of the islet and secrete glucagon, somatostatin and a pancreatic polypeptide, respectively. Little is known about the molecular and genetic factors regulating the lineage of the different endocrine cells. Pancreas development is known to be abolished in Pdx1-mutant mice and Pax4 mutants lack insulin-producing beta-cells. Here we show that the paired-box gene Pax6 is expressed during the early stages of pancreatic development and in mature endocrine cells. The pancreas of Pax6 homozygous mutant mice lack glucagon-producing cells, suggesting that Pax6 is essential for the differentiation of alpha-cells. As mice lacking Pax4 and Pax6 fail to develop any mature endocrine cells, we conclude that both Pax genes are required for endocrine fate in the pancreas.

The mammalian pancreas contains two distinct cell populations: endocrine cells which secrete hormones into the bloodstream, and exocrine cells, which secrete enzymes into the digestive tract. The four endocrine cell types found in the adult pancreas-(alpha, beta, delta and PP-synthesize glucagon, insulin, somatostatin and pancreatic polypeptide, respectively. All of these endocrine cells arise from common multipotent precursors, which coexpress several hormones when they start to differentiate. Expression of some homeobox genes in the early developing pancreas has been reported. The Pax4 gene is expressed in the early pancreas, but is later restricted to beta cells. Inactivation of Pax4 by homologous recombination results in the absence of mature insulin- and somatostatin-producing cells (beta and delta, respectively) in the pancreas of Pax4 homozygous mutant mice, but glucagon-producing alpha cells are present in considerably higher numbers. We propose that the early expression of Pax4 in a subset of endocrine progenitors is essential for the differentiation of the beta and delta cell lineages. A default pathway would explain the elevated number of alpha cells in the absence of Pax4.

Members of a family of murine octamer-binding proteins interact specifically with the octamer motif, a transcription regulatory element found in the promoter and enhancer regions of many genes. Oct-4 is a maternally expressed protein that is also present in the pre-implantation mouse embryo. Although many regulatory proteins are expressed in post-implantation embryos, transcription factors regulating pre-implantation processes have remained elusive. The Oct-4 gene is therefore a prime candidate for an early developmental control gene. Here we report the complementary DNA cloning of the mouse Oct-4 gene, and the characterization of the encoded protein(s) by sequential in vitro transcription, translation, DNA-binding and protease-clipping analysis. Deletion analysis shows that the DNA-binding activity is mediated by a POU domain encoded in an open reading frame corresponding to a 324-amino-acid protein. Sequence comparison with known POU domains reveals that Oct-4 is a novel member of the POU-family.