کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10931923 1093679 2014 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA
چکیده انگلیسی
Specification and maturation of insulin+ cells accompanies a transition in expression of Maf family of transcription factors. In development, MafA is expressed after specification of insulin+ cells that are expressing another Maf factor, MafB; after birth, these insulin+ MafA+ cells stop MafB expression and gain glucose responsiveness. Current differentiation protocols for deriving insulin-producing β-cells from stem cells result in β-cells lacking both MafA expression and glucose-stimulated insulin secretion. So driving expression of MafA, a β-cell maturation factor in endocrine precursors could potentially generate glucose-responsive MafA+ β cells. Using inducible transgenic mice, we characterized the final stages of β-cell differentiation and maturation with MafA pause/release experiments. We found that forcing MafA transgene expression, out of its normal developmental context, in Ngn3+ endocrine progenitors blocked endocrine differentiation and prevented the formation of hormone+ cells. However, this arrest was reversible such that with stopping the transgene expression, the cells resumed their differentiation to hormone+ cells, including α-cells, indicating that the block likely occurred after progenitors had committed to a specific hormonal fate. Interestingly, this delayed resumption of endocrine differentiation resulted in a greater proportion of immature insulin+MafB+ cells at P5, demonstrating that during maturation the inhibition of MafB in β-cell transitioning from insulin+MafB+ to insulin+MafB− stage is regulated by cell-autonomous mechanisms. These results demonstrate the importance of proper context of initiating MafA expression on the endocrine differentiation and suggest that generating mature Insulin+MafA+ β-cells will require the induction of MafA in a narrow temporal window to achieve normal endocrine differentiation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Developmental Biology - Volume 385, Issue 1, 1 January 2014, Pages 2-12
نویسندگان
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