Proteomics

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Ciliary tip actin dynamics regulate the cadence of photoreceptor disc formation


ABSTRACT: As signalling organelles, primary cilia regulate their membrane G protein-coupled receptor (GPCR) content by ectocytosis, a process requiring localised actin dynamics at their tip to alter membrane shape.1,2 Mammalian photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia (CC), in which photosensitive GPCRs like rhodopsin are concentrated. In an extraordinary feat of biology, outer segment discs are shed and remade daily.3 Defects in this process, due to genetic mutations, cause retinitis pigmentosa (RP), an untreatable, blinding disease. The mechanism by which photoreceptor cilia generate outer segments is therefore fundamental for vision yet poorly understood. Here, we show the membrane deformation required for outer segment disc genesis is driven by dynamic changes in the actin cytoskeleton in a process akin to ectocytosis. Further, we show RPGR, a leading causal RP gene, regulates activity of actin binding proteins crucial to this process. Disc genesis is compromised in Rpgr mouse models, slowing the actin dynamics required for timely disc formation, leading to aborted membrane shedding as ectosome-like vesicles, photoreceptor death and visual loss. Manipulation of actin dynamics partially rescues the phenotype, suggesting this pathway could be targeted therapeutically. These findings help define how actin-mediated dynamics control outer segment turnover.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Alex von kriegsheim  

LAB HEAD: a von kiregshiem

PROVIDER: PXD038015 | Pride | 2024-05-08

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
10_21_19_Roli_RPGR_KO_ROS_1.raw Raw
10_21_19_Roli_WT_ROS_1.raw Raw
10_21_19_Roli_WT_ROS_2.raw Raw
10_25_19_Roli_KO_RPGR_2.raw Raw
2018-06-28_Roly_retina01.raw Raw
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