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When cilia go bad: cilia defects and ciliopathies

A Corrigendum to this article was published on 01 January 2008

Key Points

  • Cilia are microtubule-based hair-like organelles that extend from the surface of almost all cell types of the human body. They have been adapted as versatile tools for various tissue-specific (motile and sensory) functions during development, morphogenesis and homeostasis, explaining why cilia-related disorders (ciliopathies) can affect many organ systems.

  • During early embryonic development, the rotational movement of nodal cilia at the ventral pole of the murine embryo creates a leftward fluid flow (nodal flow), which is involved in determination of the left–right body asymmetry. However, current nodal flow hypotheses cannot completely explain the complex laterality defects (heterotaxia) that are observed in humans and mice with inborn ciliary motility defects.

  • Sensory cilia act as cellular antennae to sense environmental and morphogenic cues, for example, during development. Current concepts of cilia-mediated signalling mechanisms comprise the Hedgehog signalling pathway, the Wnt/planar cell polarity pathways, receptor-mediated signalling and mechanosensory mechanisms.

  • Ciliary dysfunction is the cause of an increasing number of single organ diseases and complex syndromic forms including hydrocephalus, infertility, airway diseases, polycystic diseases of the kidney, liver and pancreas, as well as retinal diseases and defects of hearing and smell.

  • In contrast to other cell organelles, cilia are usually only assembled when cells reach a stationary or quiescent and/or differentiated state, and re-entry into the cell cycle is preceded by ciliary resorption. Therefore, cilia assembly–disassembly seems to be closely linked to cell-cycle regulation, and malfunction of these processes is involved in oncogenesis.

  • The identification of the components involved in cilia-specific functions and of the molecular mechanisms underlying the various ciliopathies are likely to facilitate the development of novel therapeutic strategies.

Abstract

Defects in the function of cellular organelles such as peroxisomes, lysosomes and mitochondria are well-known causes of human diseases. Recently, another organelle has also been added to this list. Cilia — tiny hair-like organelles attached to the cell surface — are located on almost all polarized cell types of the human body and have been adapted as versatile tools for various cellular functions, explaining why cilia-related disorders can affect many organ systems. Several molecular mechanisms involved in cilia-related disorders have been identified that affect the structure and function of distinct cilia types.

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Figure 1: Ciliary dysfunction in human diseases.
Figure 2: Human laterality disorders and current models for establishing left–right asymmetry.
Figure 3: Models of cilia-generated signalling mechanisms.
Figure 4: Hydrocephalus in mice as a result of a lack of ependymal flow.
Figure 5: The mechanosensation-based cilia signalling model.
Figure 6: Structure and function of the photoreceptor-connecting cilium.

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Acknowledgements

We thank E. Davis and G. Pazour for critical evaluation of the manuscript. H.O. and M.F. are supported by the Deutsche Forschungs-Gemeinschaft. We are grateful for the collaboration with the patient support group 'PCD und Kartagener Syndrom e.V.'. We thank H. Olbrich and N.T. Loges for help with figure preparations.

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Correspondence to Heymut Omran.

Supplementary information

Supplementary informations The supplementary movies demonstrate normal sperm motility in comparison with immotile and dysmotile sperm flagella. Also shown are normal respiratory cilia function and different aberrant beating patterns of respiratory cilia, which are typically observed in patients with primary ciliary dyskinesia (PCD) and are fundamental for diagnosis. Supplementary information S1 (movie)

Human sperm cells with normal motility (AVI 3141 kb)

Supplementary information S2 (movie)

Immotile sperm cells from a PCD patient (AVI 2938 kb)

Supplementary information S3 (movie)

Dysmotile sperm cells from a PCD patient (AVI 3437 kb)

Supplementary information S4 (movie)

Human respiratory epithelial cell layer with normal ciliary beating (AVI 2559 kb)

Supplementary information S5 (movie)

Human respiratory epithelial cells with normal ciliary beating (AVI 1071 kb)

Supplementary information S6 (movie)

Immotile respiratory cilia from a PCD patient with DNAH5 mutations (AVI 1405 kb)

Supplementary information S7 (movie)

Dysmotile respiratory cilia from a PCD patient with DNAI1 mutations (AVI 2230 kb)

Supplementary information S8 (movie)

Dysmotile respiratory cilia from a PCD patient with unknown mutations (AVI 1074 kb)

Supplementary information S9 (movie)

Uncoordinated beating of respiratory cilia from a PCD patient with OFD1 mutations (AVI 1153 kb)

Related links

Related links

OMIM

ADPKD

Alstrom syndrome

ARPKD

BBS

Kartagener's syndrome

Meckel–Gruber syndrome

NPHP

orofacialdigital syndrome

PCD

Usher syndrome

DATABASES

Entrez-Gene

DNAH5

DNAI1

Ift88

Bbs1

Bbs4

Mkks

Pkd1

OFD1

RPGR

UniProtKB

polycystin-2

patched-1

GLI1

GLI2

GLI3

SUFU

SMO

FURTHER INFORMATION

Heymut Omran's homepage

Chlamydomonas Flagellar Proteome

Cilia Proteome database

Ciliomics

Primary Cilia Resource

Glossary

Intraflagellar transport

(IFT). A cilia-specific and flagella-specific transport system that relies on at least 16 different proteins that assemble into transport rafts and move ciliary components across the compartment border and along the peripheral axonemal microtubules to the ciliary tip and back to the cell body. IFT was first described in bi-flagellate green algae (Chlamydomonas reinhardtii).

Ciliogenesis

The processes of cilia assembly and growth that follow and/or accompany cell polarization.

Notochordal plate

An epithelial primordial structure of the notochord (a cylindrical rod of cells). The sheet of notochordal cells is laterally in contact with the roof of the primitive gut and dorsally in contact with the midline cells of the neural plate. The notochordal plate folds off from the roof of the primitive gut to form the notochord.

Anterograde

The transport direction from the ciliary base to the tip.

Retrograde

The transport direction from the ciliary tip back to the cell body.

Mucociliary clearance

The process by which the continuous coordinated beating of respiratory cilia moves the thin mucus layer that covers the airway epithelia towards the pharynx to defend against inhaled pathogens trapped in the mucus.

Ependymal flow

The laminar flow of cerebrospinal fluid through the brain ventricles and the cerebral aqueduct generated by the coordinated beating of ependymal cilia.

Primary ciliary dyskinesia

(PCD). A genetically and phenotypically heterogeneous group of disorders characterized by defective ciliary motility.

Nephronophthisis

An autosomal recessive cystic kidney disease characterized by normal or reduced kidney size, cysts at the corticomedullary border and predominant tubulointerstitial fibrosis. Phthisis is a Greek word meaning shrinking or wasting.

Situs inversus totalis

The complete mirror-image arrangement of all thoracic and abdominal organs.

Situs solitus

The normal position of the viscera (stomach and spleen on the left side, liver on the right side). The three-lobed lung is positioned on the right, with the two-lobed lung on the left, and the left and right cardiac atria are positioned normally.

Situs inversus abdominalis

The isolated inversion of abdominal organs, but a normal composition of thoracic organs.

Situs inversus thoracalis

The isolated inversion of thoracic organs, but a normal composition of abdominal organs.

Holoprosencephaly

A developmental disorder of the brain due to a failure of the embryonic forebrain (the prosencephalon) to form bilateral hemispheres of the cephalon. This causes defects in brain structure and function and also affects the development of the face.

Polydactyly

Supernumerary fingers or toes. The presence of six fingers or six toes on one or both hands or feet is usually called hexadactyly.

Craniofacial defects

The developmental abnormalities that affect the head or skull and structures of the face.

Bardet–Biedl syndrome

(BBS). A clinically pleiotropic disorder that has a primarily autosomal recessive inheritance pattern (twelve loci, BBS1–BBS12, have been identified so far) and a multitude of symptoms including rod–cone dystrophy, retinitis pigmentosa, obesity, polydactyly, renal abnormalities (such as cystic kidneys), learning disabilities or mental retardation, male hypogonadism and congenital heart defects. BBS proteins localize either to the ciliary base or the axoneme and are involved in subcellular targeting of ciliary proteins. Seven of the known BBS proteins assemble into a core complex called the BBSome.

Spina bifida

A developmental abnormality that results from an incomplete closure of the embryonic neural tube and an incompletely formed spinal cord that protrudes through an open gap in the unfused spines of the vertebrae (spina bifida aperta). In the milder form, spina bifida occulta, the spinal cord does not protrude because only a small part of one vertebra is missing and there is no opening to the skin.

Osteochondro-dysplasia

An abnormal growth of cartilage and bone (individual bones or group of bones). Growth defects of the long bones and/or spine usually cause shortened limbs or a disproportionately shortened body.

Metachronal wave

A wave-like movement that is propagated along the epithelial surface, created when cilia on one segment of the epithelium move after another.

Cholangiocytes

The epithelial cells of the bile ducts.

Bronchiectasis

A bag-like or cylindrical widening of parts of the bronchial tree, which is usually caused by localized injury of bronchial tissue due to bacterial infections. Affected bronchi are irreversibly damaged.

Chronic sinusitis

A permanent or recurrent inflammation of the paranasal sinuses often caused by infections.

Hypoosmia

A decreased ability to smell odours.

Anosmia

The absence of the ability to smell odours.

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Fliegauf, M., Benzing, T. & Omran, H. When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8, 880–893 (2007). https://doi.org/10.1038/nrm2278

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