FOLLISTATIN REGULATES THE RELATIVE PROPORTIONS OF ENDOCRINE VERSUS EXOCRINE TISSUE DURING PANCREATIC DEVELOPMENT

In this study, we have investigated the role of the embryonic mesenchy me In the development of the pancreas. We have compared the developmen t in vitro of E12.5 rat pancreatic rudiments grown in the presence or absence of mesenchyme. When the E12.5 pancreatic epithelial rudiment i s cultured in the presence of its surrounding mesenchyme, both morphog enesis and cytodifferentiation of the exocrine component of the pancre as are completely achieved, while only a few immature endocrine cells develop. The pancreatic rudiments grown in the absence of mesenchyme d evelop in a completely different way; the exocrine tissue develops poo rly and fails to undergo acinar morphogenesis, while the endocrine tis sue develops actively. Four times more insulin-positive cells develop after removal of the mesenchyme than in the cultures performed in the presence of mesenchyme. Moreover, the insulin-expressing cells develop ed in the mesenchyme-depleted this rudiments appear mature since they do not coexpress glucagon, express the glucose transporter Glut-2 and express Rab3A, a molecule associated with the secretory granules. More over, these endocrine cells are able to associate and form true islets . Both the inductive effect of the mesenchyme on the proper developmen t of the exocrine tissue and its repressive effect on the development of the endocrine cells are mediated by soluble factors. Follistatin, w hich is expressed by E12.5 pancreatic mesenchyme, can mimic both induc tive and repressive effects of the mesenchyme. Follistatin could thus represent one of the mesenchymal factors required for the development of the exocrine tissue while exerting a repressive role on the differe ntiation of the endocrine cells.