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M. Furimsky, Y. Wang, V.A. Wallace; The Sonic Hedgehog Pathway Regulates Retinal Progenitor Cell Proliferation And Neurogenesis . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2797.
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© ARVO (1962-2015); The Authors (2016-present)
Multipotent progenitor cells in the developing retina give rise to six neuronal and one glial cell type. Understanding how the retinal environment influences key transcriptional regulators of cell fate has implications for directing the differentiation of stem cells into specific retinal cell types. The morphogen Sonic hedgehog (Shh) functions as a signal from retinal ganglion cells (RGCs) to retinal progenitor cells to promote proliferation and regulate cell type specification. In this study, we examined the role of of the Shh pathway and its downstream effectors, the Gli transcription factors, in regulating cell proliferation and neurogenesis.
We examined gene expression, cell type specification and cell proliferation pre–natally in Shh and Gli mutant mouse embryos, as well as post–natally in mice with the Shh gene conditionally ablated from the peripheral retina.
Embryonic (E14.5) Shh mutant retinas displayed a decrease in cell proliferation, decreased expression of retinal progenitor genes and increased numbers of retinal ganglion cells (RGCs). The expression of progenitor and cell cycle progression genes is increased in the retinas of Gli3xt/xt mice, and the numbers of RGCs is decreased in the RGC layer of the retina at this developmental time–point. Cell proliferation is also markedly increased in Gli3xt/xt retinas (increased proportion of BrdU+ cells), suggesting that Gli3 normally inhibits proliferation. We then investigated whether genetic removal of Gli3 could rescue retinal defects associated with loss of Shh signalling. We find that removal of one allele of Gli3 is sufficient to restore RGC number to wildtype levels in mice with a conditional inactivation of Shh.
Our findings suggest that Shh regulates proliferation and RGC development by antagonizing Gli3 repressor activity.
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