Abstracts
1999 Digestive Disease Week

# 2159 THE ONTOGENY OF ACTIVIN B AND FOLLISTATIN IN DEVELOPING EMBRYONIC MOUSE PANCREAS: IMPLICATIONS FOR LINEAGE SELECTION.
T Maldonado, A Kadison, C Crisera, J Grau, S Alkasab, M Longaker, George K Gittes, New York Univ Med Ctr, New York, NY

Activin, a member of the TGF-beta superfamily has been shown to be a critical regulator in exocrine and endocrine pancreas differentiation. Exogenous activin completely blocks exocrine duct formation. Moreover, transgenic mice with blocked activin signaling develop hypoplasia of pancreatic endocrine islets late in gestation. Follistatin, a known inhibitor of activin, when added exogenously to in vitro developing pancreas, results in a significant overgrowth of exocrine cells and a dramatic reduction in endocrine cells. The purpose of this study was to describe the ontogeny of activin and follistatin in developing pancreas and to elucidate potential mechanisms for exocrine and endocrine lineage selection. Mouse embryonic pancreases were dissected at ages ranging from day 10 (E10.5) to 18.5 (E18.5). Pancreases were processed for histochemistry. Immunohistochemistry was performed for activin B (one of two existing isomers), follistatin, insulin, and glucagon. Activin B was absent in earlier gestational ages and first detected in E15.5 epithelia, in an identical distribution to insulin, implying a possible role for activin in endocrine differentiation. By E18.5 activin B was localized only to islets. Interestingly, in adult islets, cells staining for activin B were arranged in the mantle distribution characteristic of glucagon-secreting alpha-cells. Follistatin was found to be ubiquitous in mesenchyme at early ages, but then disappearing after E12.5. Surprisingly, follistatin reappeared in the epithelium-derived islets at E18.5 and continued to be expressed in adult islets. We propose that mesenchyme-derived follistatin inhibits epithelium-derived activin early in pancreatic development, thus allowing for unopposed exocrine differentiation, and for the relative suppression of endocrine differentiation. At later ages (E12.5-E15.5) the natural resorption of mesenchyme and resulting loss of follistatin liberates epithelial activin to induce progression of endocrine cells to form mature islets by the time of birth. The co-expression of follistatin and activin B in the postnatal islets may help to maintain endocrine homeostatis. Finally, understanding the proposed regulatory effects of follistatin and activin B may prove critical in understanding disease states of endocrine imbalance, such as diabetes mellitus or insulinoma.

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