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Chai-An Mao, Hongyan Li, Zhijing Zhang, Takae Kiyama, Satchidananda Panda, Samer Hattar, Christophe Ribelayga, Stephen Mills, Steven Wang; Regulation of ipRGCs by Tbr2. Journal of Vision 2013;13(15):P6. doi: 10.1167/13.15.41.
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© ARVO (1962-2015); The Authors (2016-present)
In mammalian retina, the non-image-forming visual system is composed of the melanopsin/Opn4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). IpRGCs were discovered as a third type of photoreceptors primarily involved in conveying tasks such as circadian photo-entrainment and pupillary light reflex (PLR). Despite a wealth of knowledge about the morphology and physiology of ipRGCs, the molecular mechanisms controlling their formation and survival are currently unknown. Recently, we discovered that Tbr2, a T-box-containing transcriptional factor, precedes the expression of Opn4 during RGC neurogenesis and that Opn4 expression is exclusively restricted to Tbr2-expressing RGCs. In addition, our preliminary data revealed that ipRGCs do not form in Tbr2−/− retinas. These results indicate that Tbr2 is a reliable molecular predictor of ipRGCs and hypothesize that a stringent epistatic relationship exists between Tbr2 and ipRGCs.
Here, we use genetically engineered conditional (Cre-lox) mouse models to show that ipRGCs do not develop when Tbr2 is deleted prior to RGC formation (Tbr2flox/flox: Six3-Cre:Opn4TauLacZ/+ and Tbr2flox/flox:Math5Cre/+). The developed ipRGCs degenerate after Tbr2 is deleted intrinsically (Tbr2flox/flox:Opn4Cre/+:Z/EG), resulting in partially defective PLR. Interestingly, as most ipRGCs degenerate in the Tbr2flox/flox:Opn4Cre/+ retina, more Tbr2+ RGCs begin to activate Opn4Cre, which subsequently deletes Tbr2flox alleles intrinsically and causes further degeneration of themselves in a cyclical manner. In comparison to the major brain targets of ipRGCs, the Tbr2+ RGCs with newly produced Opn4 project mainly to the suprachiasmatic nucleus (SCN) and intergeniculate leaflet (IGL), but rarely to olivarypretectal nucleus (OPN) (Tbr2flox/flox:Opn4Cre/TauLacZ). Taken together, our data suggest that Tbr2 is essential for the formation and maintenance of ipRGCs and that Tbr2+ RGCs are pre-established during embryonic development and can serve as a reservoir to modulate the number of ipRGCs.
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