Endocrine cells of the intestine, pancreas and adrenal gland develop from the endoderm and neural crest, respectively. Despite their different developmental origins, we discovered that these distinct endocrine cells rely on a common transcription factor, Insm1, that controls their development. The Insm1 (insulinoma-associated 1, IA-1) gene encodes a zinc-finger factor that was discovered in an insulinoma cDNA library. We show that pancreatic and intestinal endocrine cells as well as the endocrine cells of the adrenal gland express Insm1 and require Insm1 for their development. In the pancreas of Insm1 mutant mice, endocrine precursors are formed, but only few insulin-positive beta cells are generated. Instead, endocrine precursor cells accumulate that express none of the pancreatic hormones. A similar change is observed in the development of intestine and adrenal gland, where endocrine precursor cells are generated but do not differentiate correctly. A hallmark of endocrine cell differentiation is the accumulation of proteins that participate in secretion and vesicle transport, and we find many of the corresponding genes to be down-regulated in Insm1 mutant mice. Insm1 thus controls a gene expression program that comprises hormones and proteins of the secretory machinery. Our genetic analysis has revealed a key role of Insm1 in differentiation of endocrine cells.
03 - 07 May 2008
European Society of Endocrinology