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Departments of Medicine (H.Z., D.L., X.F., U.G.K., M.G.) and Molecular Physiology and Biophysics (A.M.A., M.G.), and Program in Developmental Biology (M.G.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; and Department of Biochemistry and Molecular Genetics (G.A.G., R.H.C.), University of Illinois at Chicago, Chicago, Illinois 60607
Address all correspondence and requests for reprints to: Maureen Gannon, Ph.D., Vanderbilt University Medical Center, Division of Diabetes, Endocrinology and Metabolism, 2220 Pierce Avenue, 746 PRB, Nashville, Tennessee 37232. E-mail: Maureen.gannon{at}vanderbilt.edu.
The FoxM1 transcription factor is highly expressed in proliferating cells and activates several cell cycle genes, although its requirement appears to be limited to certain tissue types. Embryonic hepatoblast-specific inactivation of Foxm1 results in a dramatic reduction in liver outgrowth and subsequent late gestation lethality, whereas inactivation of Foxm1 in adult liver impairs regeneration after partial hepatectomy. These results prompted us to examine whether FoxM1 functions similarly in embryonic outgrowth of the pancreas and ß-cell proliferation in the adult. We found that 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 was inactivated throughout the developing pancreatic endoderm by embryonic d 15.5 (Foxm1
panc). Mice lacking Foxm1 in their entire pancreas were born with normal pancreatic and ß-cell mass; however, they displayed a gradual decline in ß-cell mass with age. Failure of postnatal ß-cell mass expansion resulted in impaired islet function by 6 wk of age and overt diabetes by 9 wk. The decline in ß-cell mass in Foxm1panc animals is due to a dramatic decrease in postnatal ß-cell replication and a corresponding increase in nuclear localization of the cyclin-dependent kinase inhibitor, p27Kip1, a known target of FoxM1 inhibition. We conclude that Foxm1 is essential to maintain normal ß-cell mass and regulate postnatal ß-cell turnover. These results suggest that mechanisms regulating embryonic ß-cell proliferation differ from those used postnatally to maintain the differentiated cell population.
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