title: Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA.
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.
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, United States.
authors.forename: KaiHui Hu
authors.initials: KH
authors.lastname: He
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, United States.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Juhl
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Karadimos
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, United States.
authors.forename: Ilham
authors.initials: I
authors.lastname: El Khattabi
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, United States.
authors.forename: Connor
authors.initials: C
authors.lastname: Fitzpatrick
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, United States.
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D055098:Endocrine Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051258:MafB Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007328:Insulin; D051473:Maf Transcription Factors, Large; D051258:MafB Transcription Factor; D009419:Nerve Tissue Proteins; C485160:Mafa protein, mouse; C490406:Mafb protein, mouse; C407737:Neurog3 protein, mouse
keywords: Differentiation of endocrine progenitors; Transcription factor MafA; β-Cell maturation