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The function of the encoded protein, termed retinoschisin, and the molecular mechanisms underlying <jats:styled-content style=\"fixed-case\">XLRS<\/jats:styled-content> pathogenesis are still unresolved, although a direct interaction partner of the secreted retinoschisin, the retinal Na\/K\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase, was recently identified. Earlier gene expression studies in retinoschisin\u2010deficient (<jats:italic>Rs1h<\/jats:italic><jats:sup><jats:italic>\u2212\/Y<\/jats:italic><\/jats:sup>) mice provided a first indication of pathological up\u2010regulation of mitogen\u2010activated protein (<jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content>) kinase signalling in disease pathogenesis. To further investigate the role for retinoschisin in <jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content> kinase regulation, we exposed Y\u201079 cells and murine <jats:italic>Rs1h<\/jats:italic><jats:sup><jats:italic>\u2212\/Y<\/jats:italic><\/jats:sup> retinae to recombinant retinoschisin and the <jats:styled-content style=\"fixed-case\">XLRS<\/jats:styled-content>\u2010associated mutant <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>1\u2010C59S. Although normal retinoschisin stably bound to retinal cells, <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>1\u2010C59S exhibited a strongly reduced binding affinity. Simultaneously, exposure to normal retinoschisin significantly reduced phosphorylation of C\u2010<jats:styled-content style=\"fixed-case\">RAF<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content> kinases <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 in Y\u201079 cells and murine <jats:italic>Rs1h<\/jats:italic><jats:sup><jats:italic>\u2212\/Y<\/jats:italic><\/jats:sup> retinae. Expression of <jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content> kinase target genes <jats:italic>C\u2010<jats:styled-content style=\"fixed-case\">FOS<\/jats:styled-content><\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">EGR<\/jats:styled-content>1<\/jats:italic> was also down\u2010regulated in both model systems. Finally, retinoschisin treatment decreased pro\u2010apoptotic <jats:italic><jats:styled-content style=\"fixed-case\">BAX<\/jats:styled-content>\u20102<\/jats:italic> transcript levels in Y\u201079 cells and <jats:italic>Rs1h<\/jats:italic><jats:sup><jats:italic>\u2212\/Y<\/jats:italic><\/jats:sup> retinae. Upon retinoschisin treatment, these cells showed increased resistance against apoptosis, reflected by decreased caspase\u20103 activity (in Y\u201079 cells) and increased photoreceptor survival (in <jats:italic>Rs1h<\/jats:italic><jats:sup><jats:italic>\u2212\/Y<\/jats:italic><\/jats:sup> retinal explants). <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>1\u2010C59S did not influence C\u2010<jats:styled-content style=\"fixed-case\">RAF<\/jats:styled-content> or <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 activation, <jats:italic>C\u2010<jats:styled-content style=\"fixed-case\">FOS<\/jats:styled-content><\/jats:italic> or <jats:italic><jats:styled-content style=\"fixed-case\">EGR<\/jats:styled-content>1<\/jats:italic> expression, or apoptosis. Our data imply that retinoschisin is a novel regulator of <jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content> kinase signalling and exerts an anti\u2010apoptotic effect on retinal cells. We therefore discuss that disturbances of <jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content> kinase signalling by retinoschisin deficiency could be an initial step in <jats:styled-content style=\"fixed-case\">XLRS<\/jats:styled-content> pathogenesis.<\/jats:p>","DOI":"10.1111\/jcmm.13019","type":"journal-article","created":{"date-parts":[[2016,12,20]],"date-time":"2016-12-20T09:22:50Z","timestamp":1482225770000},"page":"768-780","source":"Crossref","is-referenced-by-count":25,"title":["The X\u2010linked juvenile retinoschisis protein retinoschisin is a novel regulator of mitogen\u2010activated protein kinase signalling and apoptosis in the retina"],"prefix":"10.1111","volume":"21","author":[{"given":"Karolina","family":"Pl\u00f6ssl","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University of Regensburg Regensburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhard 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