Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA
| Autor: | Susan Bonner-Weir, Michael J Karadimos, Kai Hui Hu He, Connor Fitzpatrick, Ilham El Khattabi, Arun Sharma, Kirstine Juhl |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Maf Transcription Factors Large medicine.medical_treatment Transgene Cellular differentiation MafB Transcription Factor Enteroendocrine cell Mice Transgenic Nerve Tissue Proteins Biology Article Mice Internal medicine Insulin-Secreting Cells Insulin Secretion medicine Basic Helix-Loop-Helix Transcription Factors Animals Insulin Pancreas Molecular Biology β-Cell maturation Transcription Factor MafA Stem Cells Gene Expression Regulation Developmental Cell Differentiation Cell Biology Differentiation of endocrine progenitors Transcription factor MafA Endocrinology MAFB Stem cell Endocrine Cells Developmental Biology |
| Zdroj: | Developmental Biology. 385(1):2-12 |
| ISSN: | 0012-1606 |
| DOI: | 10.1016/j.ydbio.2013.10.024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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