Journal
JOURNAL OF CELL BIOLOGY
Volume 192, Issue 6, Pages 1023-1041Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201012116
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Funding
- March of Dimes
- Canadian Institutes of Health Research (CIHR) [MOP-82870]
- Science Foundation Ireland
- European Commission
- NIH, Hepato/Renal Fibrocystic Diseases Core Center [P30 DK074038]
- NIH [RO1 DK065655, T32 DK007545-22]
- NSERC
- MSFHR
- Michael Smith Foundation for Health Research (MSFHR)
- European Community [241955]
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Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP), and related ciliopathies present with overlapping phenotypes and display considerable allelism between at least twelve different genes of largely unexplained function. We demonstrate that the conserved C. elegans B9 domain (MKS-1, MKSR-1, and MKSR-2), MKS-3/TMEM67, MKS-5/RPGRIP1L, MKS-6/CC2D2A, NPHP-1, and NPHP-4 proteins exhibit essential, collective functions at the transition zone (TZ), an under-appreciated region at the base of all cilia characterized by Y-shaped assemblages that link axoneme microtubules to surrounding membrane. These TZ proteins functionally interact as members of two distinct modules, which together contribute to an early ciliogenic event. Specifically, MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension and subsequently restrict accumulation of nonciliary components within the ciliary compartment. Together, our findings uncover a unified role for eight TZ-localized proteins in basal body anchoring and establishing a ciliary gate during ciliogenesis, and suggest that disrupting ciliary gate function contributes to phenotypic features of the MKS/NPHP disease spectrum.
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