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Takae Kiyama, Ling Bai, Steven W. Wang; A Near-complete Loss Of Retinal Ganglion Cells Causes Severe Reduction In All Retinal Cell Types. Invest. Ophthalmol. Vis. Sci. 2012;53(14):421.
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Retinal ganglion cells (RGCs) are the first cell type to be born during retinogenesis. In addition to their signal transmitting function in the mature visual system, they also play important roles during retinogenesis. It has been shown that RGCs affect the final cell number in a retina. Previous study comparing total cell numbers in retinas with varying degrees of RGC loss leads to a hypothesis that there is a non-linear relationship between the number of RGCs and the number of total retinal cells. To test this hypothesis and further investigate RGCs’ role in retinogenesis, we created a compound knockout mouse line with the lowest RGC number known to date.
Math5 and Brn3b are essential transcription factors for RGC formation. Knockout math5 and brn3b resulted in 95% and 80% of RGC loss respectively. brn3bdta;six3-cre mutant ablating newborn RGCs by diphtheria toxin causes 98% of developmental RGCs loss. Combinations of these mutants, a retina with near complete loss of RGCs was postulated. We, therefore, created a math5-/-;brn3bdta/dta;six3-cre mouse line to study retinogenesis in an environment with virtually no RGCs.
math5-/-;brn3bdta/dta;six3-cre retina lost virtually all RGCs. This resulted the thinnest retina ever reported. Drastic reductions of cell numbers were observed in all cell layers. Most noticeably, the outer nuclear layer was reduced to a thin line of cells becoming indistinguishable from the inner nuclear layer. Total cell numbers in the math5-/-;brn3bdta/dta;six3-cre retinas were drastically less than that of math5-/-;brn3b-/- retinas which had 99% RGC loss.
In the math5-/-;brn3bdta/dta;six3-cre retina, which has virtually no RGCs, numbers of all retinal cell types were drastically reduced comparing to a defective retina that had only 1% RGCs. Results support our hypothesis that the number of RGC forms a non-linear relationship to the number of total retinal cells. RGCs are required, directly or indirectly, for formation or maintenance of all other cell types during retinogenesis. More importantly, cumulative results indicate that retinal histogenesis is not a preprogrammed neurogenic event.
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