| First Author | He KH | Year | 2014 |
| Journal | Dev Biol | Volume | 385 |
| Issue | 1 | Pages | 2-12 |
| PubMed ID | 24183936 | Mgi Jnum | J:205335 |
| Mgi Id | MGI:5544654 | Doi | 10.1016/j.ydbio.2013.10.024 |
| Citation | Hu He K, et al. (2014) Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA. Dev Biol 385(1):2-12 |
| abstractText | 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 beta-cells from stem cells result in beta-cells lacking both MafA expression and glucose-stimulated insulin secretion. So driving expression of MafA, a beta-cell maturation factor in endocrine precursors could potentially generate glucose-responsive MafA(+) beta cells. Using inducible transgenic mice, we characterized the final stages of beta-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 alpha-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 beta-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(+) beta-cells will require the induction of MafA in a narrow temporal window to achieve normal endocrine differentiation. |
