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Primary cilia as dynamic and diverse signalling hubs in development and disease

Nature Reviews Genetics volume 24, pages 421–441 (2023)Cite this article

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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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Fig. 1: Architecture of primary cilia and main ciliary subcompartments.
Fig. 2: Overview of signalling pathways coordinated by primary cilia.
Fig. 3: Ciliary dynamics.
Fig. 4: Challenge of ciliopathies — biology across scales.

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Acknowledgements

The authors apologize to authors whose work could not be cited due to space and reference limitations. The authors thank A. Roberts and E. Lorentzen for helpful discussions and appreciate the very helpful comments and suggestions by the reviewers, which greatly improved this review. P.M. is grateful for support from the MRC (MC_U_12018/26) and from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement n°866355). S.T.C. is grateful for support from the Lundbeck Foundation (R317-2019-889), and L.B.P. acknowledges funding from the Novo Nordisk Foundation (grant #NNF18OC0053024) and Independent Research Fund Denmark (grant #2032-00115B).

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  1. These authors contributed equally: Pleasantine Mill, Søren T. Christensen.

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  1. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland

    Pleasantine Mill

  2. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Søren T. Christensen & Lotte B. Pedersen

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Glossary

Axoneme

Core structure of cilia, which usually comprises 9 outer microtubule doublets and 0 or 2 central microtubule singlets in primary (9 + 0) and motile cilia (9 + 2), respectively.

Basal body

Specialized centriole that provides the foundation of the axoneme and anchors the cilium to the cell body via distal and subdistal appendages or fibres.

BBSome

A complex composed of eight Bardet–Biedl syndrome proteins, which is thought to function as a cargo adaptor for the retrograde IFT machinery during ciliary membrane protein export.

Centriole

Barrel-shaped structure composed of 9 microtubule triplets that gives rise to the basal body and constitutes the core structure of the centrosome.

Centrosome

Main microtubule-organizing centre in animals. Composed of two centrioles (mother and daughter) surrounded by pericentriolar material.

Ciliopathy

A genetic disorder characterized by ciliary dysfunction, and whose affected gene product localizes to (first-order ciliopathy) or indirectly affects (second-order ciliopathy) the cilium–centrosome axis.

Ciliary necklace

Outer aspect of the ciliary membrane located at the transition zone region where Y-links connect the inside of the membrane to the axoneme.

Ciliary pocket

An invagination of the periciliary membrane, which is a hotspot for endocytosis and exocytosis of vesicles derived from or destined to the ciliary membrane.

Ectosomes

Extracellular vesicles that bud directly from the membrane, including the ciliary membrane.

Intraflagellar transport

(IFT). Conserved intraciliary transport system in which kinesin 2 and cytoplasmic dynein 2 motors move trains of cargo-associated IFT-A/B complexes into and out of cilia. Required for ciliary assembly, maintenance and function.

Periciliary membrane

Membrane region at the base of the cilium that connects the ciliary membrane with the plasma membrane. Sometimes invaginated to form a ciliary pocket.

Phosphoinositides

(PIPs). Lipid signalling molecules that coordinate multiple membrane-associated molecular events.

Primary cilia

Non-motile sensory organelles present on the cell surface. They typically have a 9 + 0 axoneme surrounded by a membrane enriched for specific receptors and ion channels involved in signalling.

Transition zone

(TZ). Ciliary subcompartment located between the basal body and cilium itself, which functions as a barrier for selective transport of molecules into and out of the cilium.

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Mill, P., Christensen, S.T. & Pedersen, L.B. Primary cilia as dynamic and diverse signalling hubs in development and disease. Nat Rev Genet 24, 421–441 (2023). https://doi.org/10.1038/s41576-023-00587-9

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