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T.C. Lee, N. Claros, D. Almeida, D.H. Abramson, H. Khanna, A. Swaroop, D. Cobrinik; Expression of the Retinoblastoma Protein in Human Retinal Development . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3150.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:The retinoblastoma protein (Rb) performs an essential tumor suppressor function in the developing human retina, but the cells in which Rb has this effect are unknown. This study aimed to define the Rb expression pattern in developing retina, with respect to cell cycle phase and cell type, as a means to identify cells in which Rb might suppress retinoblastoma tumorigenesis. Methods:Fetal eyes from gestational week 12–23 were obtained under New York–Prebsyterian Hospital IRB approval . Eyes were fixed and frozen sections prepared and stained for Rb using monoclonal antibody G3–245. Sections were then stained for cell proliferation markers Ki67, cyclin D1, cyclin A2, cyclin B1, PH3, and p27Kip1; or for retinal cell markers RXRgamma, Brn3a, Brn3b, Nrl, cone arrestin, CRALBP, Chx10, and calbindin. Results:Rb was prominently expressed in retinal progenitor cells (RPCs) in the G1, S, and G2 phases, coinciding with expression of cyclin D1, cyclin A2, and cytoplasmic cyclin B1, respectively. In contrast, Rb was not detected in mitotic cells as defined by expression of nuclear cyclin B1 and PH3. Similarly, Rb had minimal expression in the earliest identifiable ganglion, amacrine, and bipolar precursors, and in a subset of early RXRgamma (+) cone precursors aligned at the outer limiting membrane. Subsequently, Rb expression modestly increased in ganglion and bipolar precursors, and dramatically increased in cone precursors, but was again down–regulated during further differentiation of these cell types. Notably, Rb was co–expressed with the rod–specific transcription factor Nrl in early post–mitotic rod precursors positioned adjacent to proliferating RPCs, but had minimal expression in the majority of rod precursors or in rhodopsin (+) rods. Rb was prominently expressed in a subset of CRALBP (+) cells undergoing the transition from RPC to Muller glia, but had minimal expression in mature glial cells. Finally, Rb was generally expressed in a pattern complementary to p27Kip1, with the exception of early rod and cone precursors which transiently co–expressed these proteins. Conclusions:pRB had minimal expression in the earliest identifiable post–mitotic ganglion, amacrine, bipolar, or cone precursor cells, and thus might not mediate the initial proliferative arrest of these precursor cell types. However, Rb was clearly present in early rod and Muller glia precursors as well as late cone precursors, suggesting that Rb may suppress the outgrowth of tumors derived from these cells.
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