title: Activins A and B Regulate Fate-Determining Gene Expression in Islet Cell Lines and Islet Cells From Male Mice.
abstract: TGFβ superfamily ligands, receptors, and second messengers, including activins A and B, have been identified in pancreatic islets and proposed to have important roles regulating development, proliferation, and function. We previously demonstrated that Fstl3 (an antagonist of activin activity) null mice have larger islets with β-cell hyperplasia and improved glucose tolerance and insulin sensitivity in the absence of altered β-cell proliferation. This suggested the hypothesis that increased activin signaling influences β-cell expansion by destabilizing the α-cell phenotype and promoting transdifferentiation to β-cells. We tested the first part of this hypothesis by treating α- and β-cell lines and sorted mouse islet cells with activin and related ligands. Treatment of the αTC1-6 α cell line with activins A or B suppressed critical α-cell gene expression, including Arx, glucagon, and MafB while also enhancing β-cell gene expression. In INS-1E β-cells, activin A treatment induced a significant increase in Pax4 (a fate determining β-cell gene) and insulin expression. In sorted primary islet cells, α-cell gene expression was again suppressed by activin treatment in α-cells, whereas Pax4 was enhanced in β-cells. Activin treatment in both cell lines and primary cells resulted in phosphorylated mothers against decapentaplegic-2 phosphorylation. Finally, treatment of αTC1-6 cells with activins A or B significantly inhibited proliferation. These results support the hypothesis that activin signaling destabilized the α-cell phenotype while promoting a β-cell fate. Moreover, these results support a model in which the β-cell expansion observed in Fstl3 null mice may be due, at least in part, to enhanced α- to β-cell transdifferentiation.
authors.affiliation: Departments of Veterinary and Animal Science (D.A., A.B., A.L.S.) and Nutrition (M.L.B.), and Molecular and Cellular Biology Graduate Program (N.U.), University of Massachusetts-Amherst, Amherst, Massachusetts 01003.
authors.forename: Danielle
authors.initials: D
authors.lastname: Andrzejewski
authors.affiliation: Departments of Veterinary and Animal Science (D.A., A.B., A.L.S.) and Nutrition (M.L.B.), and Molecular and Cellular Biology Graduate Program (N.U.), University of Massachusetts-Amherst, Amherst, Massachusetts 01003.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Brown
authors.affiliation: Departments of Veterinary and Animal Science (D.A., A.B., A.L.S.) and Nutrition (M.L.B.), and Molecular and Cellular Biology Graduate Program (N.U.), University of Massachusetts-Amherst, Amherst, Massachusetts 01003.
authors.forename: Nathan
authors.initials: N
authors.lastname: Ungerleider
authors.affiliation: Departments of Veterinary and Animal Science (D.A., A.B., A.L.S.) and Nutrition (M.L.B.), and Molecular and Cellular Biology Graduate Program (N.U.), University of Massachusetts-Amherst, Amherst, Massachusetts 01003.
authors.forename: Amy
authors.initials: A
authors.lastname: Burnside
authors.affiliation: Departments of Veterinary and Animal Science (D.A., A.B., A.L.S.) and Nutrition (M.L.B.), and Molecular and Cellular Biology Graduate Program (N.U.), University of Massachusetts-Amherst, Amherst, Massachusetts 01003.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Schneyer
mesh_terms: D028341:Activins / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005934:Glucagon / Q000187:drug effects / Q000235:genetics; D050416:Glucagon-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051258:MafB Transcription Factor / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D051761:Paired Box Transcription Factors / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics
chemical_list: C469265:ARX protein, mouse; D018398:Homeodomain Proteins; C514817:Ins1 protein, mouse; D007328:Insulin; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C422405:activin A; C044147:activin B; C084010:pancreatic and duodenal homeobox 1 protein; D028341:Activins; D005934:Glucagon