Primary Cilia As Dynamic and Diverse Signalling Hubs in Development and Disease

Overview

Journal Nat Rev Genet

Specialty Genetics

Date 2023 Apr 18

PMID 37072495

Authors

Pleasantine Mill

Soren T Christensen

Lotte B Pedersen

Affiliations

Soon will be listed here.

Abstract

Primary cilia, antenna-like sensory organelles protruding from the surface of most vertebrate cell types, are essential for regulating signalling pathways during development and adult homeostasis. Mutations in genes affecting cilia cause an overlapping spectrum of >30 human diseases and syndromes, the ciliopathies. Given the immense structural and functional diversity of the mammalian cilia repertoire, there is a growing disconnect between patient genotype and associated phenotypes, with variable severity and expressivity characteristic of the ciliopathies as a group. Recent technological developments are rapidly advancing our understanding of the complex mechanisms that control biogenesis and function of primary cilia across a range of cell types and are starting to tackle this diversity. Here, we examine the structural and functional diversity of primary cilia, their dynamic regulation in different cellular and developmental contexts and their disruption in disease.

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References

Gilliam J, Chang J, Sandoval I, Zhang Y, Li T, Pittler S . Three-dimensional architecture of the rod sensory cilium and its disruption in retinal neurodegeneration. Cell. 2012; 151(5):1029-41. PMC: 3582337. DOI: 10.1016/j.cell.2012.10.038. View

Russell S, Drack A, Cideciyan A, Jacobson S, Leroy B, Van Cauwenbergh C . Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial. Nat Med. 2022; 28(5):1014-1021. PMC: 9117145. DOI: 10.1038/s41591-022-01755-w. View

Haward F, Maslon M, Yeyati P, Bellora N, Hansen J, Aitken S . Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function. Elife. 2021; 10. PMC: 8352595. DOI: 10.7554/eLife.65104. View

Gadadhar S, Alvarez Viar G, Hansen J, Gong A, Kostarev A, Ialy-Radio C . Tubulin glycylation controls axonemal dynein activity, flagellar beat, and male fertility. Science. 2021; 371(6525). PMC: 7612590. DOI: 10.1126/science.abd4914. View

Stuck M, Chong W, Liao J, Pazour G . Rab34 is necessary for early stages of intracellular ciliogenesis. Curr Biol. 2021; 31(13):2887-2894.e4. PMC: 8282653. DOI: 10.1016/j.cub.2021.04.018. View

Ma M, Tian X, Igarashi P, Pazour G, Somlo S . Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet. 2013; 45(9):1004-12. PMC: 3758452. DOI: 10.1038/ng.2715. View

Sang L, Miller J, Corbit K, Giles R, Brauer M, Otto E . Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell. 2011; 145(4):513-28. PMC: 3383065. DOI: 10.1016/j.cell.2011.04.019. View

Mukhopadhyay S, Lu Y, Qin H, Lanjuin A, Shaham S, Sengupta P . Distinct IFT mechanisms contribute to the generation of ciliary structural diversity in C. elegans. EMBO J. 2007; 26(12):2966-80. PMC: 1894762. DOI: 10.1038/sj.emboj.7601717. View

Mukhopadhyay S, Wen X, Chih B, Nelson C, Lane W, Scales S . TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes Dev. 2010; 24(19):2180-93. PMC: 2947770. DOI: 10.1101/gad.1966210. View

10.

Grisham J . CILIATED EPITHELIAL CELLS IN NORMAL MURINE INTRAHEPATIC BILE DUCTS. Proc Soc Exp Biol Med. 1963; 114:318-20. DOI: 10.3181/00379727-114-28663. View

11.

Ocbina P, Anderson K . Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev Dyn. 2008; 237(8):2030-8. PMC: 2702862. DOI: 10.1002/dvdy.21551. View

12.

Kiesel P, Alvarez Viar G, Tsoy N, Maraspini R, Gorilak P, Varga V . The molecular structure of mammalian primary cilia revealed by cryo-electron tomography. Nat Struct Mol Biol. 2020; 27(12):1115-1124. PMC: 7610599. DOI: 10.1038/s41594-020-0507-4. View

13.

Besschetnova T, Kolpakova-Hart E, Guan Y, Zhou J, Olsen B, Shah J . Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation. Curr Biol. 2010; 20(2):182-7. PMC: 2990526. DOI: 10.1016/j.cub.2009.11.072. View

14.

Lewis T, Kundinger S, Pavlovich A, Bostrom J, Link B, Besharse J . Cos2/Kif7 and Osm-3/Kif17 regulate onset of outer segment development in zebrafish photoreceptors through distinct mechanisms. Dev Biol. 2017; 425(2):176-190. PMC: 5558849. DOI: 10.1016/j.ydbio.2017.03.019. View

15.

Tripathi P, Zhu Z, Qin H, Elsherbini A, Crivelli S, Roush E . Palmitoylation of acetylated tubulin and association with ceramide-rich platforms is critical for ciliogenesis. J Lipid Res. 2020; 62:100021. PMC: 7903138. DOI: 10.1194/jlr.RA120001190. View

16.

Dyson J, Conduit S, Feeney S, Hakim S, DiTommaso T, Fulcher A . INPP5E regulates phosphoinositide-dependent cilia transition zone function. J Cell Biol. 2016; 216(1):247-263. PMC: 5223597. DOI: 10.1083/jcb.201511055. View

17.

Schmid F, Schou K, Vilhelm M, Holm M, Breslin L, Farinelli P . IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases. J Cell Biol. 2017; 217(1):151-161. PMC: 5748969. DOI: 10.1083/jcb.201611050. View

18.

Nauli S, Pala R, Kleene S . Calcium channels in primary cilia. Curr Opin Nephrol Hypertens. 2016; 25(5):452-8. PMC: 4974130. DOI: 10.1097/MNH.0000000000000251. View

19.

De-Castro A, Rodrigues D, De-Castro M, Vieira N, Vieira C, Carvalho A . WDR60-mediated dynein-2 loading into cilia powers retrograde IFT and transition zone crossing. J Cell Biol. 2021; 221(1). PMC: 8576871. DOI: 10.1083/jcb.202010178. View

20.

Masyuk A, Huang B, Ward C, Gradilone S, Banales J, Masyuk T . Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am J Physiol Gastrointest Liver Physiol. 2010; 299(4):G990-9. PMC: 2957333. DOI: 10.1152/ajpgi.00093.2010. View