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M. A. Dyer, I. Ajioka; Uncoupled Proliferation and Differentiation in Horizontal Neurons of the Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5706.
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© ARVO (1962-2015); The Authors (2016-present)
During neurogenesis, progenitor cells must exit the cell cycle, undergo cell fate specification, migrate to their appropriate layer, extend neurites and form synapses. This process is thought to be unidirectional and irreversible. The Rb family of proteins regulate progenitor cell cycle exit and neuronal differentiation in the developing retina. To test the individual contribution of each Rb family member during neurogenesis we generated mice containing a single allele of Rb (Rb-single), p107 (p107-single) or p130 (p130-single) in their developing retinas.
To analyze the developmental defects in each of these mutant retinae we performed immunostaining of retinal sections, dissociated cell scoring, real time RT-PCR, transmission electron microscopic analysis, 2-photon live imaging, lineage analysis and biochemical studies.
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 molecular and morphological features of horizontal cells including neuronal processes and synapses. These highly differentiated tumors progressed rapidly and metastasized to the lymph nodes, brain and bone marrow with the same histopathological features of human metastatic retinoblastoma.
This is the first example of metastatic retinoblastoma in the mouse. More importantly, these studies demonstrate that neuronal differentiation is not strictly unidirectional and that highly differentiated tumors can be aggressive and invasive.
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