title: Ontogeny of activin B and follistatin in developing embryonic mouse pancreas: implications for lineage selection.
abstract: Activin, a member of the transforming growth factor-beta superfamily, has been shown to be a critical regulator in exocrine and endocrine pancreas formation. The purpose of our study was to describe the ontogeny of activin B and its inhibitor, follistatin, in developing pancreas and to elucidate potential mechanisms for exocrine and endocrine lineage selection. Mouse embryonic pancreata were dissected at various ages (day 10 [E10.5] to birth [E18.5]), sectioned, and immunostained for activin B (one of two existing isomers, A and B), follistatin, insulin, and glucagon. In addition, reverse transcriptase-polymerase chain reaction was employed to determine the messenger RNA expression of follistatin in isolated pancreatic epithelia and mesenchyme of various ages. Activin B was first detected at E12.5 in epithelial cells coexpressing glucagon. At E16.5 these coexpressors appeared as clusters in close proximity to early ducts. By E18.5 activin B was localized to forming islets where cells coexpressed glucagon and were arranged in the mantle formation characteristic of mature alpha cells. Follistatin was found to be ubiquitous in pancreatic mesenchyme at early ages by immunohistochemical analysis, disappearing sometime after E12.5. Follistatin reappeared in E18.5 islets and remains expressed in adult islets. Follistatin messenger RNA was first detected in epithelium at E11.5, preceding its protein expression in islets later in gestation. We propose that mesenchyme-derived follistatin inhibits epithelium-derived activin at early embryonic ages allowing for unopposed exocrine differentiation and relative suppression of endocrine differentiation. At later ages the decrease in the amount of mesenchyme relative to epithelium and the subsequent drop in follistatin levels liberates epithelial activin to allow differentiation of endocrine cells to form mature islets by the time of birth.
authors.affiliation: Laboratory of Developmental Biology and Repair, Department of Surgery, New York University Medical Center, New York, NY, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Maldonado
authors.forename: A S
authors.initials: AS
authors.lastname: Kadison
authors.forename: C A
authors.initials: CA
authors.lastname: Crisera
authors.forename: J B
authors.initials: JB
authors.lastname: Grau
authors.forename: S L
authors.initials: SL
authors.lastname: Alkasab
authors.forename: M T
authors.initials: MT
authors.lastname: Longaker
authors.forename: G K
authors.initials: GK
authors.lastname: Gittes
mesh_terms: D028341:Activins; D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D038681:Follistatin; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006133:Growth Substances / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D009842:Oligopeptides; D010179:Pancreas / Q000196:embryology*; D010455:Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000276:Adjuvants, Immunologic; D038681:Follistatin; D006023:Glycoproteins; D006133:Growth Substances; D009842:Oligopeptides; D010455:Peptides; D012333:RNA, Messenger; C044147:activin B; D028341:Activins; C048617:myelopeptides