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Juliette Bitard, Annaïg Hamon, Christel Masson, Jerome E Roger, Muriel PERRON; Hippo pathway in Muller glia cell during retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):416.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal dystrophies are a leading cause of blindness for which there is currently no efficient cure. Among several therapeutic approaches under investigations, regeneration stimulation from endogenous stem cells holds a lot of promises. Müller cells are of particular interest because they contribute to remarkable regeneration in certain species. Even though such process is largely inefficient in mammals, Müller glia cells retain the capacity to dedifferentiate into retinal progenitors and regenerate lost photoreceptors under certain pathological conditions and stimuli. Among attractive candidates to favor Müller glia cell cycle reentry, we choose to focus on the Hippo pathway, which recently emerged as a crucial player of adult tissue regeneration.
Retinal expression patterns of key effectors of the Hippo pathway, YAP and TEAD1, were determined by qPCR, immunohistochemistry (IHC), and immunoblotting, in the Rd10 retinitis pigmentosa mouse model and compared to wild type controls. Co-labeling with proliferative cells was done by IHC after daily twice-intraperitoneal injections of BrdU. The activity of the Hippo pathway was evaluated by the analysis of (i) the physical interaction between YAP and TEAD1 as revealed by IHC, immunoprecipitation, and duolink experiments and (ii) the expression of their transcriptional target genes studied by qPCR.
YAP and TEAD1 are specifically expressed by Müller cells in the wild type retina. In Rd10 mice, Müller cells undergo gliosis and some reenter the cell cycle after the onset of degeneration. Interestingly, this degenerative context leads to a 2-fold increase in YAP and TEAD1 expression levels in reactive Müller cells compared to the wild type situation. Under such circumstances, we found that YAP and TEAD1 co-localize and interact in the nucleus of Müller cells and the expression levels of their transcriptional targets CYR61 and CTGF are increased by 4- and 2-fold respectively.
This work shows that photoreceptor degeneration is associated with an upregulation of YAP/TEAD1 expression and transcriptional activity within Müller cells. This study therefore sheds new light into the molecular mechanisms underlying Müller cell reactivation and raises the question of YAP/TEAD1 function in Müller cell reprogramming and/or cell cycle re-entry in the degenerative retina.
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