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RB and E2F in mouse retina |
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| RB and E2F in mouse retina |
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作者：Danian C… 文章来源：1Toronto Western Research Institute, Toronto, ON,CANADA 点击数： 更新时间：2005-7-12 10:37:01 
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| To examine the role of retinoblastoma protein pRB and its relative p107, and their downstream targets E2F in the development of mouse retina.Methods: Cre recombinase can be used to delete genes that have been engineered to contain two flanking loxP sites (so called ¡°floxed¡± genes). We crossed mice that have a floxed Rb allele with another strain carrying a Cre recombinase transgene under the control of the Pax6 alpha-enhancer (alpha-Cre), which is active in peripheral retinal progenitors atembryonic day 10 (E10). Rb deletion in progenitors mimics human retinoblastoma where, by definition, lesions must occur in dividing cells. These mice were also crossed with p107-deficient animals. P107 is an RB-related protein that blocks retinoblastoma in mice. Finally, because RB and its relatives mediate their effects by inhibiting E2F proteins, we determined whether defects observed in RB- or RB/p107-deficient mice could be rescued by inactivating individual E2Fs. Results: Retinal development involves multiplication of progenitor cells, ¡°birth¡± of post-mitotic
transition cells, and maturation into terminally differentiated neurons and glia. RB or RB/p107 loss did not alter progenitor proliferation or differentiation into transition
cells. However, transition cells failed to exit the cell cycle. Four ectopically dividing
RB/p107-deficient transition cell types died, but three survived and exited the cell cycle when they terminally differentiated. Rare sporadic tumors arose from naturally death-resistant transition cells that escaped growth arrest. Thus a differentiating
transition cell is the likely origin of retinoblastoma, not a progenitor or stem cell.
Moreover, post-Rb mutations seen in retinoblastoma overcome terminal differentiation induced growth-arrest, rather than death as previously postulated. We have also determined the downstream effectors of these defects. Knocking out E2F1, but not 2/3,
blocked ectopic division, apoptosis and tumorigenesis in the RB or RB/p107 deficient retina. E2F1 inactivation allowed us to study the role of RB/p107 in differentiation without the confounding effects of ectopic proliferation. Cholinergic amacrine
differentiation and cone loss were not rescued by E2F1 deletion. Remarkably E2F3 inactivation reversed the cholinergic amcrine defects, providing a novel role for the RB/E2F3 complex in neuronal differentiation. Conclusions: There are multiple cell type specific effects of RB/p107 loss in the retina, and distinct phenotypes are driven either by E2F1 (ectopic division, cell death, tumorigenesis), E2F3(differentiation of cholinergic amacrine), or as yet unidentified RB effector proteins (Cone survival).
These data expand considerably our understanding of the role of the RB pathway in retinal development andretinoblastoma.
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