Abstract
Insulinoma associated 1 (Insm1) 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 Insm1 in pancreatic endocrine cell development we generated mice with an Insm1GFPCre reporter allele and used them to study Insm1-expressing and null populations. Endocrine progenitor cells lacking Insm1 were less differentiated and exhibited broad defects in hormone production, cell proliferation and cell migration. Embryos lacking Insm1 contained greater amounts of a non-coding Neurog3 mRNA splice variant and had fewer Neurog3/Insm1 co-expressing progenitor cells, suggesting that Insm1 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 Insm1. Analysis of the function of Ripply3, an Insm1-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 Insm1 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.
Highlights
The genetic program responsible for the generation of pancreatic endocrine cells from endocrine progenitors remains incompletely understood (Oliver-Krasinski and Stoffers, 2008; Rieck et al, 2012; Stanger and Hebrok, 2013)
These findings indicate that in developing pancreatic endocrine cells Insulinoma associated 1 (Insm1) 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
Insertion of green fluorescent protein-Cre fusion protein (GFPCre) sequences into the Insm1 gene locus disrupted Insm1 protein expression, as confirmed by western blot analysis of homozygous null embryos. Mice heterozygous for this allele appeared normal, whereas animals that were homozygous for Insm1GFPCre died between E15.5 and E18.5 due to defects in catecholamine biosynthesis and secretion (Wildner et al, 2008)
Summary
The genetic program responsible for the generation of pancreatic endocrine cells from endocrine progenitors remains incompletely understood (Oliver-Krasinski and Stoffers, 2008; Rieck et al, 2012; Stanger and Hebrok, 2013). Received 10 October 2013; Accepted 26 May 2014 cells express Neurog, which encodes a master regulatory factor that activates a cascade of secondary transcription factor genes, including Insm, Neurod, Pax, Arx and Rfx. Received 10 October 2013; Accepted 26 May 2014 cells express Neurog, which encodes a master regulatory factor that activates a cascade of secondary transcription factor genes, including Insm, Neurod, Pax, Arx and Rfx6 Together, these and other transcription factors orchestrate the formation of the five endocrine cell types found in adult islets (Huang et al, 2000; Schwitzgebel et al, 2000; Gu et al, 2002; Collombat et al, 2003; Smith et al, 2003; Mellitzer et al, 2006; Soyer et al, 2010). Neurog expression coincides both with a markedly lower rate of cell proliferation and an increase in the expression of cyclin-dependent kinase inhibitors such as Cdkn1c ( p57Kip2) and Cdkn1a ( p21Cip1) (Georgia et al, 2006; Miyatsuka et al, 2011)
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