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ES Green, JL Stubbs, EM Levine; Rescue of Microophthalmia in the Ocular Retardation Mouse by Genetic Elimination of p27Kip1 . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2678.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Null mutations in the homeobox gene, Chx10, cause microophthalmia in the ocular retardation (Chx10 null) mouse and in humans. Chx10 is thought to be a positive regulator of proliferation in the retina, but the method by which it accomplishes this is unknown. p27Kip1 is a negative regulator of proliferation in the retina that is important for progenitor cell cycle exit at the onset of differentiation. We sought to determine if the defects in retinal progenitor proliferation in the Chx10 null mouse are due to p27Kip1 function. Methods: We generated mice that were double null for Chx10 and p27Kip1 and analyzed the phenotype in the developing and mature retina. Retinas were examined morphologically, and with immunohistochemistry and in situ hybridization. Results: At birth, total cell number in the Chx10 null retina is severely reduced compared to wild type, and this is correlated with a significant increase in the percentage of cells expressing p27Kip1. In Chx10, p27Kip1 double null retinas, however, total cell number was significantly rescued compared to the severe hypocellular defect of Chx10 null retinas. This phenotype appears to be specific to a rescue in proliferation since differentiation and cell death are not affected. While Chx10 null retinas lack any signs of lamination, double null retinas had normal lamination. Interestingly, bipolar cells were absent in the double null retina, which is attributable to a requirement of Chx10 that is independent of p27Kip1. Conclusion: These results demonstrate that p27Kip1 contributes to the proliferation defect of Chx10 null retinas. They also support the idea that Chx10 normally promotes bipolar cell genesis or maintenance, in addition to its role in proliferation, but show that it is not required for proper retinal lamination.
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