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Kevin Tenerelli, Xiong Zhang, Jonathan Hertz, Praseeda Venugopalan, Catalina B. Sun, Shomoukh A. Alshamekh, Jeffrey L Goldberg; Novel transcriptional mechanisms regulate visual pathway development. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3603.
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© ARVO (1962-2015); The Authors (2016-present)
What pathways specify retinal ganglion cell (RGC) fate in the developing retina? RGCs are born from multipotent retinal progenitor cells (RPCs) but little is known about the cell-autonomous mechanisms and environmental signals that specify RGC fate.
Using an in vitro differentiation model of RPCs, we screened and identified transcription factors important for RGC fate. Using knockout mice models, we further studied the mechanism of RGC specification in retina flat mounts by immunofluorescence and in human embryonic stem cells and induced pluripotent cell cultures assaying for RGC differentiation.
We found a new molecular pathway involving Sox4/Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs) and for optic nerve formation in mice in vivo, and is sufficient to differentiate human induced pluripotent stem cells into electrophysiologically active RGC-like cells. The previously described inhibitor of RGC differentiation, REST, depended on suppression of Sox4 expression. A novel soluble regulator for RGC differentiation, TGFβ superfamily member GDF-15, acted through Sox4 to induce RGC differentiation from progenitor cells. Sox4 and Sox11 interacted such that the normal SUMOylation of Sox11, which decreased its nuclear localization and suppressed its pro-RGC activity, was decreased in the absence of Sox4, allowing Sox11 to compensate for Sox4 absence.
These data define novel regulatory mechanisms for this SoxC molecular network, and suggest pro-RGC molecular manipulations with potential promise for cell replacement-based therapies for glaucoma and other optic neuropathies.
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