Ciliary tip actin dynamics regulate photoreceptor outer segment integrity

Roly Megaw (), Abigail Moye, Zhixian Zhang, Fay Newton, Fraser McPhie, Laura C. Murphy, Lisa McKie, Feng He, Melissa K. Jungnickel, Alex Kriegsheim, Peter A. Tennant, Chloe Brotherton, Christine Gurniak, Alecia K. Gross, Laura M. Machesky, Theodore G. Wensel and Pleasantine Mill
Additional contact information
Roly Megaw: Western General Hospital
Abigail Moye: Baylor College of Medicine
Zhixian Zhang: Baylor College of Medicine
Fay Newton: Western General Hospital
Fraser McPhie: Western General Hospital
Laura C. Murphy: Western General Hospital
Lisa McKie: Western General Hospital
Feng He: Baylor College of Medicine
Melissa K. Jungnickel: Western General Hospital
Alex Kriegsheim: University of Edinburgh
Peter A. Tennant: Western General Hospital
Chloe Brotherton: Western General Hospital
Christine Gurniak: Karlrobert-Kreiten-Strasse
Alecia K. Gross: University of Alabama at Birmingham
Laura M. Machesky: CRUK Scotland Institute
Theodore G. Wensel: Baylor College of Medicine
Pleasantine Mill: Western General Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48639-w

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