Insmi promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3

摘要

Insulinoma associated 1 (Insmi) plays an important role in regulating the development of cells in the central and peripheral nervous systems, olfactory epithelium and endocrine pancreas. To better define the role of Insmi in pancreatic endocrine cell development we generated mice with an lnsm1GFPCre reporter allele and used them to study Insmi-expressing and null populations. Endocrine progenitor cells lacking Insmi were less differentiated and exhibited broad defects in hormone production, cell proliferation and cell migration. Embryos lacking Insmi contained greater amounts of a non-coding Neurog3 mRNA splice variant and had fewer Neurog3/lnsm1 co-expressing progenitor cells, suggesting that Insmi positively regulates Neurog3. Moreover, endocrine progenitor cells that express either high or low levels of Pdx1, and thus may be biased towards the formation of specific cell lineages, exhibited cell type-specific differences in the genes regulated by Insmi. Analysis of the function of Ripply3, an smf-regulated gene enriched in the Pdx1-high cell population, revealed that it negatively regulates the proliferation of early endocrine cells. Taken together, these findings indicate that in developing pancreatic endocrine cells Insmi promotes the transition from a ductal progenitor to a committed endocrine cell by repressing a progenitor cell program and activating genes essential for RNA splicing, cell migration, controlled cellular proliferation, vasculogenesis, extracellular matrix and hormone secretion.