title: Hedgehog regulates Norrie disease protein to drive neural progenitor self-renewal.
abstract: Norrie disease (ND) is a congenital disorder characterized by retinal hypovascularization and cognitive delay. ND has been linked to mutations in 'Norrie Disease Protein' (Ndp), which encodes the secreted protein Norrin. Norrin functions as a secreted angiogenic factor, although its role in neural development has not been assessed. Here, we show that Ndp expression is initiated in retinal progenitors in response to Hedgehog (Hh) signaling, which induces Gli2 binding to the Ndp promoter. Using a combination of genetic epistasis and acute RNAi-knockdown approaches, we show that Ndp is required downstream of Hh activation to induce retinal progenitor proliferation in the retina. Strikingly, Ndp regulates the rate of cell-cycle re-entry and not cell-cycle kinetics, thereby uncoupling the self-renewal and cell-cycle progression functions of Hh. Taken together, we have uncovered a cell autonomous function for Ndp in retinal progenitor proliferation that is independent of its function in the retinal vasculature, which could explain the neural defects associated with ND.
authors.affiliation: Vision Program, Ottawa Hospital Research Institute, Ottawa, Ont. K1H 8L6, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: McNeill
authors.forename: Chantal
authors.initials: C
authors.lastname: Mazerolle
authors.forename: Erin A
authors.initials: EA
authors.lastname: Bassett
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mears
authors.forename: Randy
authors.initials: R
authors.lastname: Ringuette
authors.forename: Pamela
authors.initials: P
authors.lastname: Lagali
authors.forename: David J
authors.initials: DJ
authors.lastname: Picketts
authors.forename: Kim
authors.initials: K
authors.lastname: Paes
authors.forename: Dennis
authors.initials: D
authors.lastname: Rice
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Wallace
mesh_terms: D000818:Animals; D001766:Blindness / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D004843:Epistasis, Genetic; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D040181:Genetic Diseases, X-Linked; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012160:Retina / Q000254:growth & development / Q000378:metabolism*; D012162:Retinal Degeneration; D012171:Retinal Vessels / Q000254:growth & development / Q000378:metabolism; D013036:Spasms, Infantile / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D000075746:Zinc Finger Protein Gli2
chemical_list: D005136:Eye Proteins; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D000075746:Zinc Finger Protein Gli2