Intraflagellar transport: from molecular characterisation to mechanism

Blacque, Oliver E.; Cevik, Sebiha; Kaplan, Oktay I.

doi:10.2741/2871

Cited by 83 publications

(80 citation statements)

References 114 publications

(263 reference statements)

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“…An alternative explanation is that Bbs mutations might cause a loss of cargo from the IFT complex or abnormal cargo loading. It has been proposed that BBS proteins facilitate cargo loading at the basal body or ciliary transition zone and/or stabilize IFT-cargo interactions (15,36). In these cases, instability of the IFT-cargo complex might lead to premature dissociation and protein buildup in the cilium.…”

Section: Discussionmentioning

confidence: 99%

Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

Shah

Farmen²,

Moninger³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

108

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Mutations in a group of genes that contribute to ciliary function cause Bardet-Biedl syndrome (BBS). Most studies of BBS have focused on primary, sensory cilia. Here, we asked whether loss of BBS proteins would also affect motile cilia lining the respiratory tract. We found that BBS genes were expressed in human airway epithelia, and BBS2 and BBS4 localized to cellular structures associated with motile cilia. Although BBS proteins were not required for ciliogenesis, their loss caused structural defects in a fraction of cilia covering mouse airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia. We discovered this same misshapen appearance in airway cilia from Bbs1, Bbs2, Bbs4, and Bbs6 mutant mice. The structural abnormalities were accompanied by functional defects; ciliary beat frequency was reduced in Bbs mutant mice. Previous reports suggested BBS might increase the incidence of asthma. However, compared with wild-type controls, neither airway hyperresponsiveness nor inflammation increased in Bbs2 Ϫ/Ϫ or Bbs4 ؊/؊ mice immunized with ovalbumin. Instead, these animals were partially protected from airway hyperresponsiveness. These results emphasize the role of BBS proteins in both the structure and function of motile cilia. They also invite additional scrutiny of motile cilia dysfunction in patients with this disease.asthma ͉ basal body

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Section: Discussionmentioning

confidence: 99%

Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

Shah

Farmen²,

Moninger³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

108

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“…Anterograde ciliary transport is driven by kinesin-2 (22), and cells lacking the Kif3a subunit cannot form primary cilia or respond to ShhN (23). We therefore transfected Kif3a −/− MEFs with Arhgap36, variable amounts of exogenous Kif3a, and the Gli-dependent luciferase reporter.…”

Section: Significancementioning

confidence: 99%

Arhgap36-dependent activation of Gli transcription factors

Rack¹,

Ni²,

Payumo³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are upregulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.

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“…Like all microtubule-based structures, ciliary axonemes are built of heterodimers of a-and b-tubulins, highly conserved small GTP-binding proteins. The recruitment of other cilium components, including signal transduction machinery, requires a conserved assembly and maintenance process called intraflagellar transport (IFT) (Blacque et al 2008;Pedersen and Rosenbaum 2008). IFT employs two major complexes that transport ciliary cargo bidirectionally by traveling along the axonemal microtubules.…”

mentioning

confidence: 99%

Specific α- and β-Tubulin Isotypes Optimize the Functions of Sensory Cilia inCaenorhabditis elegans

Hurd

Miller²,

Núñez

et al. 2010

Genetics

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Primary cilia have essential roles in transducing signals in eukaryotes. At their core is the ciliary axoneme, a microtubule-based structure that defines cilium morphology and provides a substrate for intraflagellar transport. However, the extent to which axonemal microtubules are specialized for sensory cilium function is unknown. In the nematode Caenorhabditis elegans, primary cilia are present at the dendritic ends of most sensory neurons, where they provide a specialized environment for the transduction of particular stimuli. Here, we find that three tubulin isotypes-the a-tubulins TBA-6 and TBA-9 and the b-tubulin TBB-4-are specifically expressed in overlapping sets of C. elegans sensory neurons and localize to the sensory cilia of these cells. Although cilia still form in mutants lacking tba-6, tba-9, and tbb-4, ciliary function is often compromised: these mutants exhibit a variety of sensory deficits as well as the mislocalization of signaling components. In at least one case, that of the CEM cephalic sensory neurons, cilium architecture is disrupted in mutants lacking specific ciliary tubulins. While there is likely to be some functional redundancy among C. elegans tubulin genes, our results indicate that specific tubulins optimize the functional properties of C. elegans sensory cilia.

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Intraflagellar transport: from molecular characterisation to mechanism

Cited by 83 publications

References 114 publications

Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

Arhgap36-dependent activation of Gli transcription factors

Specific α- and β-Tubulin Isotypes Optimize the Functions of Sensory Cilia inCaenorhabditis elegans

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