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

5 years ago

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

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

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.

Publisher URL: http://dx.doi.org/10.1038/ncb3599

DOI: 10.1038/ncb3599