title: Progranulin regulates neurogenesis in the developing vertebrate retina.
abstract: We evaluated the expression and function of the microglia-specific growth factor, Progranulin-a (Pgrn-a) during developmental neurogenesis in the embryonic retina of zebrafish. At 24 hpf pgrn-a is expressed throughout the forebrain, but by 48 hpf pgrn-a is exclusively expressed by microglia and/or microglial precursors within the brain and retina. Knockdown of Pgrn-a does not alter the onset of neurogenic programs or increase cell death, however, in its absence, neurogenesis is significantly delayed-retinal progenitors fail to exit the cell cycle at the appropriate developmental time and postmitotic cells do not acquire markers of terminal differentiation, and microglial precursors do not colonize the retina. Given the link between Progranulin and cell cycle regulation in peripheral tissues and transformed cells, we analyzed cell cycle kinetics among retinal progenitors following Pgrn-a knockdown. Depleting Pgrn-a results in a significant lengthening of the cell cycle. These data suggest that Pgrn-a plays a dual role during nervous system development by governing the rate at which progenitors progress through the cell cycle and attracting microglial progenitors into the embryonic brain and retina. Collectively, these data show that Pgrn-a governs neurogenesis by regulating cell cycle kinetics and the transition from proliferation to cell cycle exit and differentiation. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 77: 1114-1129, 2017.
authors.affiliation: Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, 48105.|Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, 48105.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Walsh
authors.affiliation: Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, 48105.|Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, 48105.
authors.forename: Peter F
authors.identifier: 0000-0001-9454-2684
authors.initials: PF
authors.lastname: Hitchcock
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000077153:Progranulins
chemical_list: D001973:Bromodeoxyuridine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050761:Cyclin-Dependent Kinase Inhibitor p57; D016213:Cyclins; D049452:Green Fluorescent Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D029961:Zebrafish Proteins; C509429:grna protein, zebrafish; D000077153:Progranulins
keywords: CNS development; Progranulin-a; cell cycle; retinal development; zebrafish