MRC Human Genetics Unit, MRC Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
Princess Alexandra Eye Pavilion, NHS Lothian, Edinburgh, EH3 9HA, UK.
Nat Commun. 2024 May 21;15(1):4316. doi: 10.1038/s41467-024-48639-w.
As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily. Defects in this process, due to mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, the mechanism of photoreceptor disc generation is poorly understood. Here, we show membrane deformation required for disc genesis is driven by dynamic actin changes in a process akin to ectocytosis. We show RPGR, a leading RP gene, regulates actin-binding protein activity central to this process. Actin dynamics, required for disc formation, are perturbed in Rpgr mouse models, leading to aborted membrane shedding as ectosome-like vesicles, photoreceptor death and visual loss. Actin manipulation partially rescues this, suggesting the pathway could be targeted therapeutically. These findings help define how actin-mediated dynamics control outer segment turnover.
作为信号细胞器，纤毛通过胞吐作用来调节其 G 蛋白偶联受体的含量，这一过程需要局部的肌动蛋白动力学来改变膜的形状。光感受器外节由尖端高度特化的连接纤毛中的折叠膜（盘）组成，感光 GPCR 集中于此。盘片每天都会脱落和重新形成。由于突变，该过程中的缺陷会导致色素性视网膜炎（RP）。虽然这对视力至关重要，但光感受器盘生成的机制还知之甚少。在这里，我们表明，盘发生所必需的膜变形是由类似于胞吐作用的过程中动态肌动蛋白变化驱动的。我们表明，RP 基因中的主要基因 RPGR 调节着这一过程中核心的肌动蛋白结合蛋白活性。在 Rpgr 小鼠模型中，形成盘所需的肌动蛋白动力学受到干扰，导致膜脱落为类似胞吐体的小泡，光感受器死亡和视力丧失。肌动蛋白的操作部分挽救了这一点，这表明该途径可能成为治疗的靶点。这些发现有助于定义肌动蛋白介导的动力学如何控制外节的更替。
