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Xiaoliang L. Xu, David Abramson, Suresh Jhanwar, David Cobrinik; Rb1 Knockdown Selectively Induces Cone Precursor Proliferation Dependent On Cone Specific Signaling In Fetal Retinal Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5362.
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© ARVO (1962-2015); The Authors (2016-present)
Retinoblastomas are thought to result from the inactivation of RB1 in the developing human retina. We previously found that retinoblastoma has properties of a cone precursor tumor and depends on cone-related signaling proteins such as TRB2, MDM2, and N-Myc. These findings provided strong, yet indirect evidence for a cone precursor retinoblastoma origin. Here, we tested whether human cone precursors are uniquely sensitive to Rb inactivation, in a manner that depends on cone-specific circuitry, or Skp2 and Rb-related proteins, whose relevance to human retinoblastoma has not been fully explored.
We knocked down RB1 in human fetal retinal cells, either with or without co-knockdown of cone or Rb-related proteins, and examined proliferation of different cell types by labeling and co-staining for EdU, Ki67, and retinal cell type-specific markers, including Crx, L/M opsin, cone arrestin, TRB2, Pax6, Nestin, CRALBP, Sox2, ChX10, Prox1, Brn3b, Pax2, and Nrl.
RB1 knockdown induced proliferation and expression of Ki67 in L/M opsin+ and Crx+ cone precursors and induced apoptosis of Muller glia and retinal progenitor cells, but did not induce Ki67 expression in other retinal cell types. Co-knockdown of RB1 with TRB2, MDM2, N-Myc, SKP2, or p107 blocked the cone proliferation, whereas co-knockdown with p130 promoted proliferation. All of the proliferating cones had failed to label with a proliferating cell marker (EdU) prior to RB1 knockdown, indicating that they derived from non-proliferating cells.
These results indicate that Rb is required to suppress the proliferation of post-mitotic human cone precursors but not other retinal types. As for retinoblastoma cells, the Rb-deficient cone precursor proliferation depended on the cone factors TRB2, N-Myc, MDM2, and SKP2; but did not depend on RXR-gamma. Surprisingly, p107 appears to promote, whereas p130 suppresses, Rb-depleted cone proliferation. These findings provide further support for a cone precursor origin of retinoblastoma.
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