title: 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 Insm1(GFPCre) 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.
authors: Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Anna B
authors: AB
authors: Osipovich
authors: Department of Animal Science, Cornell University, Ithaca, NY 14850, USA.
authors: Qiaoming
authors: Q
authors: Long
authors: Penn Center for Bioinformatics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Elisabetta
authors: E
authors: Manduchi
authors: Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Rama
authors: R
authors: Gangula
authors: Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Susan B
authors: SB
authors: Hipkens
authors: Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Judsen
authors: J
authors: Schneider
authors: Department of Laboratory Animal Science, Kitasato University School of Medicine, Sagamihara, 252-0374, Japan.
authors: Tadashi
authors: T
authors: Okubo
authors: Penn Center for Bioinformatics, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Christian J
authors: CJ
authors: Stoeckert
authors: Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan.
authors: Shinji
authors: S
authors: Takada
authors: Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA mark.magnuson@vanderbilt.edu.
authors: Mark A
authors: MA
authors: Magnuson
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D002469:Cell Separation; D004268:DNA-Binding Proteins / Q000502:physiology*; D055098:Endocrine Cells / Q000166:cytology*; D005109:Extracellular Matrix / Q000378:metabolism; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010179:Pancreas / Q000196:embryology; D012313:RNA / Q000378:metabolism; D012326:RNA Splicing; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D012313:RNA; D012097:Repressor Proteins; D014157:Transcription Factors; C477059:Insm1 protein, mouse; C407737:Neurog3 protein, mouse; C000591566:Ripply3 protein, mouse
keywords: Endocrine progenitor cells; Gene expression; Mouse; Pancreas development; Transcription factors