Journal Article

Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome

Van De Weghe, Julie C., Doherty, Dan, Huang, Bo, McGorty, Ryan, Pazour, Gregory J., Shi, Xiaoyu, Reiter, Jeremy F., Garcia, Galo

2017

Overview

Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition-zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS. Shi et al.  map the ciliary transition zone by STORM imaging, characterizing protein arrangements in nested rings and finding that mutations in RPGRIP1L that are associated with the ciliopathy Joubert syndrome disrupt SMO ciliary localization.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/1 / 14/34 / 14/63 / 631/1647/328/2238 / 631/80/128/1383 / 631/80/304 / Abnormalities, Multiple - genetics / Abnormalities, Multiple - metabolism / Abnormalities, Multiple - pathology / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Adolescent / Adult / Animal behavior / Animals / Architecture / Brain / Cancer Research / Care and treatment / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell Biology / Cell Line / Cellular proteins / Cellular signal transduction / Cerebellum - abnormalities / Cerebellum - metabolism / Cerebellum - pathology / Child / Cilia - metabolism / Cilia - pathology / Ciliopathies - genetics / Ciliopathies - metabolism / Ciliopathies - pathology / Congenital defects / Development and progression / Developmental Biology / Disruption / Eye Abnormalities - genetics / Eye Abnormalities - metabolism / Eye Abnormalities - pathology / Female / Gene mutations / Genetic aspects / Genetic Predisposition to Disease / Health aspects / Humans / Image Processing, Computer-Assisted / Joubert syndrome / Kidney Diseases, Cystic - genetics / Kidney Diseases, Cystic - metabolism / Kidney Diseases, Cystic - pathology / Life Sciences / Localization / Male / Meckel's syndrome / Membrane proteins / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice, Inbred C57BL / Microscopy / Microscopy, Fluorescence - methods / Mutation / Nephronophthisis / Neurodevelopmental disorders / Patched-1 Receptor - genetics / Patched-1 Receptor - metabolism / Phenotype / Protein composition / Proteins / Retina - abnormalities / Retina - metabolism / Retina - pathology / Signal Transduction / Signaling / Smoothened Receptor - genetics / Smoothened Receptor - metabolism / Stem Cells / Stochastic Processes / Young Adult