Diabetes mellitus results from inadequate insulin production from pancreatic islet Beta-cells. Treatment demands an understanding of the genetic mechanisms governing pancreas differentiation and function. PBX1 is a homeodomain factor shown in vitro to regulate pancreas gene expression along with the homeodomain proteins IPF 1 and MEIS2. Unlike 1PF1, which is expressed broadly in embryonic posterior foregut endoderm, PBX1 is found only m pancreatic endoderm at certain times. Pbxl inactivation in mice prevents islet development suggesting that PBX1 is essential for pancreas specification and endocrine function. Our specific rims are: (1) Construct transgenic mice to ectopically express wild-type and nuclear forms of PBX1 in IPFl-expressing cells in order to determine if PBX1, in cooperation with IPF1, is sufficient to induce ectopic pancreatic development. (2) Construct transgenic mice misexpressing wild type and dominant negative MEIS2 to determine if MEIS2 regulates PBX1 and IPF1 function (3) Identify pancreas-specific roles of PBX1 by conditionally inactivating PBX1 in pancreatic tissues using a conditional loxP allele of Pbx1 and Cre recombinase expressing mice.
