Ontogeny of activin B and follistatin in developing embryonic mouse pancreas: Implications for lineage selection

Activin, a member of the transforming growth factor-beta superfamily, has b een shown to be a critical regulator in exocrine and endocrine pancreas for mation. The purpose of our study was to describe the ontogeny of activin B and its inhibitor, follistatin, in developing pancreas and to elucidate pot ential mechanisms for exocrine and endocrine lineage selection. Mouse embry onic pancreata were dissected at various ages (day 10 [E10.5] to birth [E18 .5]), sectioned, and immunostained for activin B (one of two existing isome rs, A and B), follistatin, insulin, and glucagon. Tn addition, reverse tran scriptase-polymerase chain reaction was employed to determine the messenger RNA expression of follistatin in isolated pancreatic epithelia and mesench yme of various ages. Activin B was first detected at E12.5 in epithelial ce lls coexpressing glucagon. At E16.5 these coexpressors appeared as clusters in close proximity to early ducts. By E18.5 activin B was localized to for ming islets where cells coexpressed glucagon and were arranged in the mantl e 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 follistat in inhibits epithelium-derived activin at early embryonic ages allowing for unopposed exocrine differentiation and relative suppression of endocrine d ifferentiation. At later ages the decrease in the amount of mesenchyme rela tive to epithelium and the subsequent drop in follistatin levels liberates epithelial activin to allow differentiation of endocrine cells to form matu re islets by the time of birth.