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I. Ajioka, R. Martins, I. Bayazitov, D. Johnson, S. Donovan, S. Zakharenko, M. Dyer; Uncoupled Horizontal Cell Proliferation and Differentiation Lead to Metastatic Retinoblastoma in Mice. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5701.
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The protein product of the retinoblastoma susceptibility gene (Rb), Rb, and the related p107 and p130 proteins regulate transitions between cell proliferation and terminal differentiation. Although they all bind to E2F family that regulates the expression of numerous genes needed for cell cycle progression, some E2F family proteins specifically bind to the specific Rb family protein, suggesting that each Rb family protein has both specific and unique functions. Using Cre-expressing retroviruses and a retinal progenitor-specific Cre transgenic mouse line mated to Rblox mice, we previously showed that a cell-autonomous requirement for Rb at specific developmental stages in retinal progenitor cells and rod photoreceptors (Zhang, J. et al. (2004) Nat. Genet. 36, 351-360). On the other hand, we found the compensational effects of Rb and p107 on retinal progenitor cells (Donovan, S.L. et al. (2006) BMC Biol. 4, 14).
To elucidate the individual role of the Rb family proteins during retinal development, we are generating and analyzing single-allele Rb (Rb-single), p107 (p107-single) or p130 (p130-single) mice on Rb conditional and both p107 and p130 knockout mouse line.
Horizontal cells in p107-single retinae exited the cell cycle, committed to the horizontal cell fate, migrated to the inner nuclear layer, extended neurites and formed synapses. Several days later, the p107-single horizontal cells re-entered the cell cycle, clonally expanded and formed retinoblastoma while maintaining their horizontal cell molecular and morphological features including neuronal processes and synapses. These highly differentiated tumors progressed rapidly and metastasized to the parenchymal region of brain with the same histopathological features of human metastatic retinoblastoma.
These studies demonstrate that neuronal differentiation is not strictly unidirectional and that highly differentiated tumors can be aggressive and invasive.
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