The X-linked juvenile retinoschisis protein retinoschisin is a novel regulator of mitogen-activated protein kinase signalling and apoptosis in the retina.

Karolina Plössl,Ulrike Friedrich,Bernhard H.F Weber

doi:10.1111/jcmm.13019

Karolina Plössl, Ulrike Friedrich + Show 1 more

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https://doi.org/10.1111/jcmm.13019

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Abstract

X‐linked juvenile retinoschisis (XLRS) is a hereditary retinal dystrophy in young males, caused by mutations in the RS1 gene. The function of the encoded protein, termed retinoschisin, and the molecular mechanisms underlying XLRS pathogenesis are still unresolved, although a direct interaction partner of the secreted retinoschisin, the retinal Na/K‐ATPase, was recently identified. Earlier gene expression studies in retinoschisin‐deficient (Rs1h −/Y) mice provided a first indication of pathological up‐regulation of mitogen‐activated protein (MAP) kinase signalling in disease pathogenesis. To further investigate the role for retinoschisin in MAP kinase regulation, we exposed Y‐79 cells and murine Rs1h −/Y retinae to recombinant retinoschisin and the XLRS‐associated mutant RS1‐C59S. Although normal retinoschisin stably bound to retinal cells, RS1‐C59S exhibited a strongly reduced binding affinity. Simultaneously, exposure to normal retinoschisin significantly reduced phosphorylation of C‐RAF and MAP kinases ERK1/2 in Y‐79 cells and murine Rs1h −/Y retinae. Expression of MAP kinase target genes C‐FOS and EGR1 was also down‐regulated in both model systems. Finally, retinoschisin treatment decreased pro‐apoptotic BAX‐2 transcript levels in Y‐79 cells and Rs1h −/Y retinae. Upon retinoschisin treatment, these cells showed increased resistance against apoptosis, reflected by decreased caspase‐3 activity (in Y‐79 cells) and increased photoreceptor survival (in Rs1h −/Y retinal explants). RS1‐C59S did not influence C‐RAF or ERK1/2 activation, C‐FOS or EGR1 expression, or apoptosis. Our data imply that retinoschisin is a novel regulator of MAP kinase signalling and exerts an anti‐apoptotic effect on retinal cells. We therefore discuss that disturbances of MAP kinase signalling by retinoschisin deficiency could be an initial step in XLRS pathogenesis.

Highlights

Pathogenic alterations affecting the RS1 gene on chromosome Xp22.1 have been shown to cause X-linked juvenile retinoschisis (XLRS) (OMIM #312700) [1], a macular degeneration disorder in young males with a prevalence of approximately 1:5000 to 1:20,000 [2]
The authors found in the murine Rs1hÀ/Y retinae increased phosphorylation of extracellular-signal-regulated kinases 1 and 2 (Erk1/2), as well as up-regulated expression of Egr1, a prominent target gene of activated mitogen-activated protein (MAP) kinases [56]
Western blot analyses showed an increase in c-Raf and Erk1/2 phosphorylation in Rs1hÀ/Y retinae compared with wild-type retina (Fig. 1A)

Summary

Introduction

Pathogenic alterations affecting the RS1 gene on chromosome Xp22.1 have been shown to cause XLRS (OMIM #312700) [1], a macular degeneration disorder in young males with a prevalence of approximately 1:5000 to 1:20,000 [2]. A characteristic splitting of retinal layers, presenting as a bilateral foveal schisis, is found at an early stage of the disease and results in cystic degeneration of the central retina [3,4,5,6]. Comparable pathological features are evident in XLRS mice, generated via a targeted disruption of the murine orthologue of RS1, the Rs1h gene [8,9,10]. Due to the close resemblance of the retinal phenotype in Rs1h knockout mice and XLRS patients, the retinoschisin-deficient mouse represents an excellent disease model widely used in experimental studies addressing the mechanisms of XLRS pathology and novel treatment approaches [11,12,13,14,15,16]

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