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Dev Biol. 2014 Jan 1;385(1):2-12. doi: 10.1016/j.ydbio.2013.10.024. Epub 2013 Oct 29.

Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA.

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  • 1Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, United States.

Erratum in

  • Dev Biol. 2014 Feb 15;386(2):484-5.

Abstract

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.

© 2013 Published by Elsevier Inc.

KEYWORDS:

Differentiation of endocrine progenitors; Transcription factor MafA; β-Cell maturation

PMID:
24183936
[PubMed - indexed for MEDLINE]
PMCID:
PMC3918466
Free PMC Article
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