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Super-resolution microscopy reveals that disruption of ciliary transition zone architecture is a cause of Joubert syndrome

Xiaoyu Shi, Galo Garcia III, Julie C. Van De Weghe, Ryan McGorty, Gregory J. Pazour, Dan Doherty, Bo Huang, Jeremy F. Reiter
doi: https://doi.org/10.1101/142042
Xiaoyu Shi
2Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA
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Galo Garcia III
3Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA
4Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
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Julie C. Van De Weghe
5Department of Pediatrics, University of Washington Medical Center, Seattle, WA 98195, USA
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Ryan McGorty
2Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA
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Gregory J. Pazour
6Program in Molecular Medicine, University of Massachusetts Medical School, Biotech II, Suite 213, 373 Plantation Street, Worcester, MA, USA
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Dan Doherty
5Department of Pediatrics, University of Washington Medical Center, Seattle, WA 98195, USA
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Bo Huang
2Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA
3Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA
8Chan Zuckerberg Biohub, San Francisco, CA 94158 USA
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  • For correspondence: bo.huang@ucsf.edu jeremy.reiter@ucsf.edu
Jeremy F. Reiter
3Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA
4Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
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  • For correspondence: bo.huang@ucsf.edu jeremy.reiter@ucsf.edu
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ABSTRACT

Diverse human ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a ciliary domain near its base. The transition zone controls the protein composition of the ciliary membrane, but how it does so is unclear. To better understand the transition zone and its connection to ciliopathies, we defined the arrangement of key proteins in the transition zone using two-color stochastic optical reconstruction microscopy (STORM). This mapping revealed that NPHP and MKS complex components form nested rings comprised of nine-fold doublets. The NPHP complex component RPGRIP1L forms a smaller diameter transition zone ring within the MKS complex rings. JBTS-associated mutations in RPGRIP1L disrupt the architecture of the MKS and NPHP rings, revealing that vertebrate RPGRIP1L has a key role in organizing transition zone architecture. JBTS-associated mutations in TCTN2, encoding an MKS complex component, also displace proteins of the MKS and NPHP complexes from the transition zone, revealing that RPGRIP1L and TCTN2 have interdependent roles in organizing transition zone architecture. To understand how altered transition zone architecture affects developmental signaling, we examined the localization of the Hedgehog pathway component SMO in human fibroblasts derived from JBTS-affected individuals. We found that diverse ciliary proteins, including SMO, accumulate at the transition zone in wild type cells, suggesting that the transition zone is a way station 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, disrupting developmental signaling in JBTS.

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Posted May 25, 2017.
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Super-resolution microscopy reveals that disruption of ciliary transition zone architecture is a cause of Joubert syndrome
Xiaoyu Shi, Galo Garcia III, Julie C. Van De Weghe, Ryan McGorty, Gregory J. Pazour, Dan Doherty, Bo Huang, Jeremy F. Reiter
bioRxiv 142042; doi: https://doi.org/10.1101/142042
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Super-resolution microscopy reveals that disruption of ciliary transition zone architecture is a cause of Joubert syndrome
Xiaoyu Shi, Galo Garcia III, Julie C. Van De Weghe, Ryan McGorty, Gregory J. Pazour, Dan Doherty, Bo Huang, Jeremy F. Reiter
bioRxiv 142042; doi: https://doi.org/10.1101/142042

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