Key Points
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Over the past 10 years, primary cilia have been found to be required for hedgehog (Hh) signalling during development and have been implicated in cystic kidney disease and complex inherited disorders called ciliopathies.
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In early vertebrate embryos, the primary cilium seems to be dedicated to transduction of Hh signals. Proteins required for building cilia, including the anterograde kinesin-2 motor, components of the intraflagellar transport B (IFTB) complex and a subset of basal-body-associated proteins, are required for Hh signalling in mice and zebrafish, and core components of the Hh pathway localize to cilia in a ligand-dependent manner. By contrast, the evidence suggests that other developmental signalling pathways do not depend on cilia.
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All Hh signalling in embryos, adult stem cells and tumours depends on the primary cilium.
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Based on the phenotypes of mutants that lack different components of the IFT machinery, regulated trafficking within the cilium determines the level of Hh signalling.
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The fused (FU) and KIF7 proteins provide links between IFT and cilia and the Hh pathway. FU and COS2 (the homologue of KIF7) are required for Hh signalling in Drosophila melanogaster, whereas in other invertebrates they are required for ciliogenesis. In vertebrates, FU and KIF7 function in both cilia formation and Hh signalling.
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Planar cell polarity (PCP) pathways can control the position of primary cilia, and mammalian homologues of proteins that function as PCP effectors in D. melanogaster are required for ciliogenesis. These connections between PCP and cilia position may have a role in cilia function in the inner ear and in the kidney.
Abstract
The primary cilium has recently stepped into the spotlight, as a flood of data show that this organelle has crucial roles in vertebrate development and human genetic diseases. Cilia are required for the response to developmental signals, and evidence is accumulating that the primary cilium is specialized for hedgehog signal transduction. The formation of cilia, in turn, is regulated by other signalling pathways, possibly including the planar cell polarity pathway. The cilium therefore represents a nexus for signalling pathways during development. The connections between cilia and developmental signalling have begun to clarify the basis of human diseases associated with ciliary dysfunction.
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Acknowledgements
This work was funded by US National Institutes of Health grant NS044385 (to K.V.A.). S.C.G. is an American Cancer Society postdoctoral fellow.
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Glossary
- Ciliopathies
-
Human disorders affecting diverse organ systems in which the underlying cellular defect has been found to be structural or functional abnormalities of cilia.
- Basal bodies
-
Cylindrical, microtubule-based structures at the base of cilia from which ciliary axonemes are nucleated. They are derived from mother centrioles.
- Axoneme
-
The long projection of the cilium into the extracellular space. It is composed of a circular array of nine microtubule doublets.
- Anterograde trafficking
-
Transport towards the microtubule plus end (the cilia tip).
- Retrograde trafficking
-
Transport towards the microtubule minus end (the cilia base).
- Mother centriole
-
Centrioles are tube-shaped structures composed of nine triplets of microtubules. One of the two centrioles is the mother centriole, which forms the basal body.
- Polydactyly
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The formation of additional digits on the limbs. Additional posterior digits are referred to as postaxial, and additional anterior digits are referred to as preaxial.
- Pericentriolar material
-
A network of fibres and associated proteins that surround the centriole and contain the microtubule-organizing activity of the centrosome.
- Hydrocephalus
-
The build-up of cerebrospinal fluid within the ventricles of the brain.
- Kinome
-
The set of protein kinases in the genome of a given organism.
- Metazoan
-
Multicellular organisms that, with the exception of sponges, have specialized cell types. Historically referred to as the kingdom 'Animalia'.
- Convergent extension
-
A morphogenetic movement characterized by the intercalation and elongation of cells, which causes a structure to generally become longer and thinner.
- Subventricular zone
-
A layer of cells lining the ventricles of the brain in which neurogenesis takes place in adult mammals.
- Kupffer's vesicle
-
A ciliated organ of the fish embryo that serves to generate asymmetry during development, functioning analogously to the mammalian node.
- Hair cells
-
The sensory cells in the vertebrate auditory system. They are contained within the cochlea.
- Organ of Corti
-
The organ in the mammalian inner ear that contains the hair cells.
- Cochlea
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The portion of the inner ear that contains the sensory organs of hearing.
- Kinocilium
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The specialized primary cilium of the hair cells of the cochlea.
- Stereocilia
-
The actin-based sensory organelles that form a polarized chevron-shaped structure in the hair cell.
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Goetz, S., Anderson, K. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11, 331–344 (2010). https://doi.org/10.1038/nrg2774
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DOI: https://doi.org/10.1038/nrg2774
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