Hongjie Zhang's Research
FOXM1 AND REGULATION OF BETA CELL MASS
Genes and signaling pathways involved in maintaining or altering beta cell mass are candidates for disease-associated factors in diabetic individuals. We observed that the cell cycle transcription factor FoxM1 is highly expressed in embryonic and neonatal endocrine cells, when many of these cells are proliferating. Using a Cre-lox strategy, we generated mice in which FoxM1 is inactivated throughout the developing pancreatic endoderm by e15.5. Mice lacking FoxM1 in their entire pancreas areborn with normal pancreatic and beta cell mass. However, mutant male mice display a gradual decline in beta cell mass with age. At six weeks of age, many FoxM1 mutant male mice show an impaired ability to clear blood glucose during an intraperitoneal glucose tolerance test. At nine weeks of age, a significant number of FoxM1 mutant male mice are overtly diabetic. The decline in beta cell mass in FoxM1 mutant mice is due to a dramatic decrease in postnatal beta cell replication. We conclude that FoxM1 is essential to maintain normal beta cell mass and regulates beta cell turnover in the adult.