title: Dicer1 is required to repress neuronal fate during endocrine cell maturation.
abstract: MicroRNAs (miRNAs) are important regulators of gene expression programs in the pancreas; however, little is known about the role of miRNA pathways during endocrine cell specification and maturation during neonatal life. In this study, we deleted Dicer1, an essential RNase for active miRNAs biogenesis, specifically from NGN3+ endocrine progenitor cells. We found that deletion of Dicer1 in endocrine progenitors did not affect the specification of hormone-expressing endocrine cells. However, the islets in the mutant mice in the neonatal period exhibited morphological defects in organization and loss of hormone expression, and the mutant mice subsequently developed diabetes. Dicer1-deficient β-cells lost insulin expression while maintaining the expression of β-cell transcription factors such as Pdx1 and Nkx6.1 early in the postnatal period. Surprisingly, transcriptional profiling showed that that the Dicer1-deficient endocrine cells expressed neuronal genes before the onset of diabetes. The derepression of neuronal genes was associated with a loss in binding of the neuronal transcriptional repressor RE-1-silencing transcription factor to its targets in Dicer1-deficient β-cells. These studies suggest that miRNAs play a critical role in suppressing neuronal genes during the maturation of endocrine cells.
authors: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors: Murtaza S
authors: MS
authors: Kanji
authors: Martin G
authors: MG
authors: Martin
authors: Anil
authors: A
authors: Bhushan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003433:Crosses, Genetic; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D053487:DEAD-box RNA Helicases; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D043244:Ribonuclease III; C407737:Neurog3 protein, mouse; C509781:Dicer1 protein, mouse
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