The FoxM1 transcription factor is required to maintain pancreatic beta-cell mass.
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 beta-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(Deltapanc)). Mice lacking Foxm1 in their entire pancreas were born with normal pancreatic and beta-cell mass; however, they displayed a gradual decline in beta-cell mass with age. Failure of postnatal beta-cell mass expansion resulted in impaired islet function by 6 wk of age and overt diabetes by 9 wk. The decline in beta-cell mass in Foxm1(Deltapanc) animals is due to a dramatic decrease in postnatal beta-cell replication and a corresponding increase in nuclear localization of the cyclin-dependent kinase inhibitor, p27(Kip1), a known target of FoxM1 inhibition. We conclude that Foxm1 is essential to maintain normal beta-cell mass and regulate postnatal beta-cell turnover. These results suggest that mechanisms regulating embryonic beta-cell proliferation differ from those used postnatally to maintain the differentiated cell population.
Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Hongjie
H
Zhang
Amanda M
AM
Ackermann
Galina A
GA
Gusarova
David
D
Lowe
Xue
X
Feng
Usa G
UG
Kopsombut
Robert H
RH
Costa
Maureen
M
Gannon
D000818:Animals; D049109:Cell Proliferation; D048429:Cell Size; D015536:Down-Regulation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D015870:Gene Expression; D005951:Glucose Tolerance Test; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D007515:Islets of Langerhans / Q000002:abnormalities / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010179:Pancreas / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology
D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D007328:Insulin; D014157:Transcription Factors; C045073:Cre recombinase; D019426:Integrases