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Annaïg HAMON, Jerome E Roger, Juliette Bitard, christel Masson-Garcia, Elodie Grellier, Muriel PERRON; Müller cell-derived YAP signaling as a new neuroprotective pathway in the degenerating retina. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4202.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal Müller cells are essential for retinal homeostasis and mediate neuroprotection as they release neurotrophic factors during retinal degeneration. The Hippo/YAP signaling pathway has recently emerged as an important regulator of tissue homeostasis through its action on both cell proliferation and survival. Since we recently showed that YAP is specifically expressed in Müller cells, we decided to explore its role in the mouse retina, using a conditional knockout strategy, under both physiological and pathological degenerative conditions.
We crossed Rax-CreERT2; Ai9 mice (Pak et al., Plos One, 2014) with Yapflox/flox mice (Reginensi et al., Plos Genetics, 2013) to generate Yap1 conditional knockout in Müller cells. Deletion of Yap1 was induced by intra-peritoneal injection of hydroxy-tamoxifen (4-OHT, 1mg) at P10. We used N-methyl-N-nitrosourea (MNU, 60mg/kg) intra-peritoneal injections to induce photoreceptor death at P30. Retinal phenotypes were analyzed using quantitative real-time PCR, Western blot, immunohistochemistry and TUNEL essay.
Under physiological conditions and up to 1 month, we did not observe any major retinal defects following Yap deletion in Müller cells. However, in retinas with MNU-induced photoreceptor degeneration, we found that the loss of YAP in Müller cells leads to an increased number of apoptotic photoreceptor cells compared to control mice 16 hrs after injection. In addition, we showed by qPCR that the expression of GFAP, a gliosis marker, is also increased. Finally, following MNU injection in mice lacking Yap expression in Müller cells, we observed a two-fold decrease of Cyr61 expression, a direct target of YAP, compared to control animals.
All together, our results reveal that the absence of YAP in Müller cells accelerates the MNU-induced photoreceptor cell death. This suggests that YAP may be involved in the neuroprotective response of reactive Müller glia to retinal injury. Based on our results and the recent pro-survival activity of Cyr61 recently shown in the retina (Kucharska et al., Journal of Neurochemistry, 2014), we propose a model where YAP neuroprotective function in Müller cells would be mediated by Cyr61.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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