期刊
HUMAN MOLECULAR GENETICS
卷 22, 期 5, 页码 1005-1016出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds505
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资金
- Natural Sciences and Engineering Council of Canada
- Canadian Cancer Society (National Cancer Institute of Canada) [016435]
- Cancer Research Society
- Foundation Fighting Blindness Canada
- Canadian Institutes of Health Research
Norrie disease (ND) is a congenital disorder characterized by retinal hypovascularization and cognitive delay. ND has been linked to mutations in oNorrie 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.
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