How RPGR sets the rhythm of actin dynamics at the connecting cilium during photoreceptor disc formation

Led by our amazing clinician scientist Roly Megaw, we are excited to share our latest paper on BioRXiv: ‘Ciliary tip actin dynamics regulate the cadence of photoreceptor disc formation.’ This was the result of great collaborations with Wensel lab (BCM Houston, US) and Machesky lab (Beatson Institute, UK), where we used in vivo cryo-electron tomography, advanced live imaging, novel reporter mice and humanised mouse models to show how photoreceptor discs are formed and why patients lose their sight when this goes wrong.

In a remarkable biological feat, photoreceptors regrow their outer segments every week, to ensure normal vision. Our sub-tomogram averaging studies definitively show that actin filaments extend into newly forming discs to regulate this process. RPGR mutations cause inherited retinal dystrophies; the leading cause of visual loss in children and working adults. We show RPGR regulates the disassembly of these actin filaments where discs form and patient mutations prevent this, leading to reduced actin disassembly.

As a result, discs cannot form and are instead shed as extracellular vesicles, causing photoreceptor death and sight loss. Excitingly, pharmacological targeting of the actin skeleton can reduce the number of shed vesicles. This study, funded by Wellcome, sheds real light on a fundamental biological process and, perhaps more importantly, an untreatable disease. Further work will determine if this could be developed into a realistic therapeutic strategy.