Insm1 promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3

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.

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…150 Insulinoma associated 1 (Insm1) has also been identified as a regulator of a network of genes involved in endocrine differentiation including Ngn3. 151 …”

A Prominent Couple

“…INSM1 recruits cyclin D1 and histone deacetylase 3 (HDAC3) leading to altered histone H3/4 acetylation and reduced promoter activity of target genes [70]. Further, concordant mechanisms in the endocrine differentiation of β-cells and NED in PCa have been suggested [71][72][73]. INSM1 was shown to co-occupy regulatory sequences that maintain the gene expression program in endocrine β-cells together with the bHLH protein NEUROD1 and FoxA2.…”

“…Absent AR expression and disproportional low PSA levels are hallmarks of NEPC [70,71]. NE foci exist within virtually all human prostate adenocarcinomas, reported incidence rates range from 25-90% [67,72,73]. It was suggested that the different morphologic manifestations of NEPC, i.e.…”

“…carcinoid tumors, large cell neuroendocrine carcinomas and small cell carcinomas, represent a continuum characterized by gradual expression of molecular aberrations [74]. Small cell carcinoma of the prostate (Figure 1.1B), the most aggressive form of NEPC, where transformation towards a predominantly neuroendocrine histology occurred, is rare with a reported frequency of less than 1% [72]. The increasing incidence of NEPC (about 6.8% per year between 2004-2011) can be partly attributed to prolonged patients' life expectancy and aggressive rebiopsy practice of metastatic CRPC [71,75].…”

“…In 2014, the highest incidence rates for PCa in the US were in the age group of [65][66][67][68][69][70][71][72][73][74] years, while between 1975-1995 the incidence rates were in the group of 75 years or older indicating that the diagnosis is currently made at younger age [7]. The incidence rates for PCa are highly variable between different geographical areas, with highest incidence in industrialized countries [6].…”