Proendocrine genes coordinate the pancreatic differentiation program in vitro

Rosa Gasa, Caroline Mrejen, Nathaniel Leachman, Marc Otten, Michael Barnes, Juehu Wang, Swarup Chakrabarti, Raghavendra Mirmira, Michael German

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

In the developing pancreas, the basic helix-loop-helix (bHLH) protein Neurogenin2 (Ngn3) specifies which precursor cells ultimately will become endocrine cells and initiates the islet differentiation program. NeuroD1, a closely related bHLH protein and a downstream target of Ngn3, maintains the differentiation program initiated by Ngn3. We have developed an in vitro model of Ngn3-dependent differentiation by infecting pancreatic duct cell lines with an Ngn3-expressing adenovirus. We found that both Ngn3 and its downstream target NeuroD1 activated the islet differentiation program in these cells by inducing the expression of genes with early roles in the differentiation cascade, as well as genes characteristic of fully differentiated islet cells. Induction of these genes, as exemplified by the insulin1 gene, involved alteration of the local chromatin structure. Interestingly, the subsets of genes activated by Ngn3 and NeuroD1 were not completely overlapping, indicating that these two bHLH proteins serve specific functions in the development of the endocrine pancreas. In addition, microarray gene expression analysis identified a previously uncharacterized group of Ngn3-induced genes with potentially important roles in islet development and function. These studies demonstrate how Ngn3 initiates islet differentiation and provide us with a model for testing methods for producing islet cells for people with diabetes.

Original languageEnglish (US)
Pages (from-to)13245-13250
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number36
DOIs
StatePublished - Sep 7 2004

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