期刊
DEVELOPMENTAL BIOLOGY
卷 333, 期 1, 页码 108-120出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2009.06.029
关键词
MafA; Pancreas; beta-cell; Insulin gene transcription factor; Endocrine differentiation; Pancreatic development
资金
- NIH [RO1 DK060127]
- Harvard Stem Cell Institute
- Juvenile Diabetes Research Foundation (JDRF)
- JDRF postdoctoral fellowship
- Mary K. Iacocca Fellowship
- Media and Advanced Microscopy Cores of Joslin Diabetes Endocrinology Research Center [NIH DK-36836]
The transcription factor MafA regulates glucose-responsive expression of insulin. MafA-deficient mice have a normal proportion of insulin(+) cells at birth but develop diabetes gradually with age, suggesting that MafA is required for maturation and not specification of pancreatic beta-cells. However, several studies show that ectopic expression of MafA may have a role in specification as it induces insulin(+) cells in chicken gut epithelium, reprograms adult murine acinar cells into insulin(+) cells in combination with Ngn3 and Pdx1, and triggers the lens differentiation. Hence, we examined whether MafA can induce specification of beta-cells during pancreatic development. When the MafA transgene is expressed in Pdx1(+) pancreatic progenitors, both pancreatic mass and proliferation of progenitors are reduced, at least partially due to induction of cyclin kinase inhibitors p27 and p57. Expression of MafA in Pdx1(+) cells until E12.5 was sufficient to cause these effects and to disproportionately inhibit the formation of endocrine cells in the remnant pancreas. Thus, in mice, MafA expression in Pdx1(+) pancreatic progenitors is not sufficient to specify insulin(+) cells but in fact deters pancreatic development and the differentiation of endocrine cells. These findings imply that MafA should be used to enhance maturation, rather than specification, of beta-cells from stem/progenitor cells. (C) 2009 Elsevier Inc. All rights reserved.
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