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Justin Brodie-Kommit, Hope Shi, Fuguo Wu, Tiffany M Schmidt, Xiuqian Mu, Joshua H Singer, Samer Hattar; Overturning the role of Math5 in Retinal Ganglion Cell Specification. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1766.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ganglion cells (RGCs) are the sole conduits of light information to the brain. RGC differentiation occurs by retinal progenitor cells expressing transcription factors in a developmentally temporal fashion, including Math5 (Atoh7). Math5, a bHLH transcription factor, is thought to be necessary for RGC specification; since Math5 null mice lack 95% of RGCs. A recent publication, however, used lineage tracing to show that a subset of RGCs do not express Math5. Therefore, we re-examined the Math5 null mouse line on a background that prevents RGC death by knocking out the proapoptotic gene, Bax. Mutations in Math5 are responsible for multiple retinal pathologies, including arPHPV where the fetal hyaloid vasculature fails to regress and the retinal vasculature does not form, occurring in both humans and mice. Understanding its role in retinal development is key to understanding the development of the retina.
We utilized Math5-/-, Bax-/-, and the Math5-tTA;tetO-Pou4f2-Isl1 mouse lines combined with multielectrode array recordings and immunofluorescence staining to analyze RGC and retinal development.
Surprisingly, we found that even in the absence of Math5 and Bax, substantial numbers of retinal progenitor cells differentiate into RGCs and express RGC specific genes such as Brn3a, Brn3b, Isl1, and RBPMS. These rescued RGCs fail to exit the eye and form an optic nerve, yet by multielectrode array recordings, RGCs from Math5/Bax double knockout animals displayed ON, OFF and ON/OFF rod/cone light responses. We also found that even when RGC numbers in Math5/Bax double knockout animals are mostly restored, the retinal vasculature deficits were not rescued. To test whether Math5 or the optic nerve is required for the formation of the retinal vasculature we used a published mouse line where Brn3b and Islet1 are ectopically expressed from the Math5 promoter in the absence of Math5. This rescues RGC numbers and optic nerve in the absence of Math5, and surprisingly the hyaloid regression was observed and the retinal vasculature was mostly restored.
These data suggest that a subset of RGCs could be specified in the absence of Math5 and that Math5 is required for RGC differentiation in that subset by preventing apoptosis. These data also suggest that rescuing the optic nerve and RGC numbers, but not RGC numbers alone, is required for hyaloid regression and the following retinal vasculature development.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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