Functional implication of Dp71 in osmoregulation and vascular permeability of the retina.

Functional alterations of Müller cells, the principal glia of the retina, are an early hallmark of most retina diseases and contribute to their further progression. The molecular mechanisms of these reactive Müller cell alterations, resulting in disturbed retinal homeostasis, remain largely unknown. Here we show that experimental detachment of mouse retina induces mislocation of the inwardly rectifying potassium channels (Kir4.1) and a downregulation of the water channel protein (AQP4) in Müller cells. These alterations are associated with a strong decrease of Dp71, a cytoskeleton protein responsible for the localization and the clustering of Kir4.1 and AQP4. Partial (in detached retinas) or total depletion of Dp71 in Müller cells (in Dp71-null mice) impairs the capability of volume regulation of Müller cells under osmotic stress. The abnormal swelling of Müller cells In Dp71-null mice involves the action of inflammatory mediators. Moreover, we investigated whether the alterations in Müller cells of Dp71-null mice may interfere with their regulatory effect on the blood-retina barrier. In the absence of Dp71, the retinal vascular permeability was increased as compared to the controls. Our results reveal that Dp71 is crucially implicated in the maintenance of potassium homeostasis, in transmembraneous water transport, and in the Müller cell-mediated regulation of retinal vascular permeability. Furthermore, our data provide novel insights into the mechanisms of retinal homeostasis provided by Müller cells under normal and pathological conditions.

Rhodopsin maturation defects induce photoreceptor death by apoptosis: a fly model for RhodopsinPro23His human retinitis pigmentosa.

rhodopsin mutations result in autosomal dominant retinitis pigmentosa (ADRP), the most frequent being Proline-23 substitution by histidine (RhoP23H). Although cellular and rodent animal models have been developed, the pathogenic mechanisms leading to RhoP23H-induced cell death are still poorly understood. For this, we have used a Drosophila model by introducing a mutation in the fly rhodopsin-1 gene (Rh1P37H) that corresponds to human RhoP23H. Rh1P37H transgenic flies show dominant photoreceptor degeneration that mimics age-, light-dependent and progressive ADRP. Moreover, we clarify the pathogenic mechanism of Rh1P37H mutation that acts as an antimorph. First, we show the dual-localization of mutant Rhodopsin since most of Rh1P37H accumulates in endoplasmic reticulum. Second, expression of mutant, mislocalized, Rhodopsin leads to cytotoxicity, via the activation of two stress-specific mitogen-activated protein kinases (MAPKs), p38 and JNK, which are known to control stress-induced apoptosis. In Rh1P37H flies, visual loss and degeneration are indeed accompanied by apoptotic features and prevented by expression of p35 apoptosis inhibitor. Finally, we show for the first time that properly localized, mutant, Rhodopsin is active. Thus, the development of a fly model that faithfully reproduces the human disease sheds light onto the molecular defects causing ADRP thereby making it possible to devise potential therapeutic approaches.