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Hedgehog regulates Norrie disease protein to drive neural progenitor self-renewal.
McNeill, Brian; Mazerolle, Chantal; Bassett, Erin A; Mears, Alan J; Ringuette, Randy; Lagali, Pamela; Picketts, David J; Paes, Kim; Rice, Dennis; Wallace, Valerie A.
Afiliação
  • McNeill B; Vision Program, Ottawa Hospital Research Institute, Ottawa, Ont. K1H 8L6, Canada.
Hum Mol Genet ; 22(5): 1005-16, 2013 Mar 01.
Article em En | MEDLINE | ID: mdl-23201751
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.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Retina / Espasmos Infantis / Cegueira / Fatores de Transcrição Kruppel-Like / Proteínas do Olho / Via de Sinalização Wnt / Proteínas do Tecido Nervoso / Doenças do Sistema Nervoso Limite: Animals / Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Retina / Espasmos Infantis / Cegueira / Fatores de Transcrição Kruppel-Like / Proteínas do Olho / Via de Sinalização Wnt / Proteínas do Tecido Nervoso / Doenças do Sistema Nervoso Limite: Animals / Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Canadá