Show simple item record

dc.contributor.authorShi, Xiaoyu
dc.contributor.authorGarcia III, Galo
dc.contributor.authorVan De Weghe, Julie C.
dc.contributor.authorUniversity of California, San Francisco
dc.contributor.authorPazour, Gregory J.
dc.contributor.authorDoherty, Dan
dc.contributor.authorHuang, Bo
dc.contributor.authorReiter, Jeremy F.
dc.date2022-08-11T08:08:23.000
dc.date.accessioned2022-08-23T15:53:18Z
dc.date.available2022-08-23T15:53:18Z
dc.date.issued2017-05-25
dc.date.submitted2018-06-18
dc.identifier.citation<p>bioRxiv 142042; doi: https://doi.org/10.1101/142042. <a href="https://doi.org/10.1101/142042" target="_blank">Link to preprint on bioRxiv service.</a></p>
dc.identifier.doi10.1101/142042
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29326
dc.description.abstractDiverse 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.
dc.language.isoen_US
dc.relationNow published in Nature Cell Biology doi: 10.1038/ncb3599
dc.rightsThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectcell biology
dc.subjectciliopathies
dc.subjectJoubert syndrome
dc.subjecttransition zone
dc.subjectmutations
dc.subjectproteins
dc.subjectstochastic optical reconstruction microscopy
dc.subjectSTORM
dc.subjectTCTN2
dc.subjectMeckel syndrome
dc.subjectnephronophthisis
dc.subjectCell Biology
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectGenetic Phenomena
dc.titleSuper-Resolution Microscopy Reveals That Disruption Of Ciliary Transition Zone Architecture Is A Cause Of Joubert Syndrome [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2562&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1552
dc.identifier.contextkey12333954
refterms.dateFOA2022-08-23T15:53:18Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathfaculty_pubs/1552
dc.contributor.departmentProgram in Molecular Medicine


Files in this item

Thumbnail
Name:
142042.full.pdf
Size:
4.486Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC 4.0 International license.