( cell mass is dynamic, changing throughout the life of the organism in response to metabolic alterations and demands. Increases in ( cell mass are thought to occur via both replication of existing ( cells and (( cell neogenesis from stem cell progenitors. Diabetes results from an absolute (Type 1) or relative (Type 2) inadequate functional ( cell mass. Thus, genes and pathways involved in maintaining or altering ( cell mass are candidates for being affected in diabetic individuals. Functional analysis of these genes may lead to new therapeutic strategies for increasing existing ( cell mass in diabetic patients and/or facilitate the production of ( cells in vitro from embryonic or stem cells. The Foxm1 transcription factor is highly expressed in proliferating cells and activates cell cycle genes. Liver-specific Foxm1 inactivation impairs liver regeneration following partial hepatectomy. These results prompted us to examine whether Foxm1 functions similarly in pancreas and/or ( cell regeneration and compensation. We found that Foxm1 is highly expressed in embryonic and neonatal endocrine cells, when many of cells are proliferating. Using a Cre-lox strategy, we made mice with a pancreas-specific Foxm1 deletion to examine its role in pancreas regeneration following partial pancreatectomy. Mice lacking Foxm1 in their entire pancreas were glucose intolerant at 6 weeks of age and overtly diabetic by 9 weeks of age, suggesting an unexpected role for Foxm1 in normal ( cell function. Examination of mutant pancreata revealed a gradual loss of ( cell mass between 4 and 9 weeks of age. We hypothesize that Foxm1 is essential to maintain normal ( cell mass and regulate ( cell turnover. We predict that Foxm1 is critical for pancreas and ( cell regeneration and for ( cell compensation. To test these hypotheses we will inactivate Foxm1 in the entire pancreas, or exclusively in pancreatic endocrine cells. We will test the requirement for Foxm1 in different models of ( cell mass expansion including pregnancy and high fat diet/insulin resistance. A thorough understanding of Foxm1 regulation of ( cell mass may lead to strategies for maintaining ( cell mass and enhancing ( cell proliferation in diabetics. ? ? ?
