Ciliary Vesicle Formation: A Prelude to Ciliogenesis

Yee, Laura; Reiter, Jeremy F.

doi:10.1016/j.devcel.2015.03.012

Cited by 17 publications

(14 citation statements)

References 11 publications

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“…Primary cilia are microtubule-based cell surface projections that serve as signalling platforms for a number of developmentally important pathways [ 33 ]. Initiation of ciliogenesis requires vesicular trafficking of the mother centriole to, and subsequent docking with, the plasma membrane [ 34 , 35 ]. The docked centriole, known as the basal body, nucleates elongation of the ciliary axoneme by serving as a scaffold for ciliary-cargo containing vesicles [ 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

“…Initiation of ciliogenesis requires vesicular trafficking of the mother centriole to, and subsequent docking with, the plasma membrane [ 34 , 35 ]. The docked centriole, known as the basal body, nucleates elongation of the ciliary axoneme by serving as a scaffold for ciliary-cargo containing vesicles [ 34 , 35 ]. Elongation of the axoneme occurs via microtubule trafficking by intraflagellar proteins attached to kinesin and dynein motors [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

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A Point Mutation in p190A RhoGAP Affects Ciliogenesis and Leads to Glomerulocystic Kidney Defects

et al. 2016

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Rho family GTPases act as molecular switches regulating actin cytoskeleton dynamics. Attenuation of their signaling capacity is provided by GTPase-activating proteins (GAPs), including p190A, that promote the intrinsic GTPase activity of Rho proteins. In the current study we have performed a small-scale ENU mutagenesis screen and identified a novel loss of function allele of the p190A gene Arhgap35, which introduces a Leu1396 to Gln substitution in the GAP domain. This results in decreased GAP activity for the prototypical Rho-family members, RhoA and Rac1, likely due to disrupted ordering of the Rho binding surface. Consequently, Arhgap35-deficient animals exhibit hypoplastic and glomerulocystic kidneys. Investigation into the cystic phenotype shows that p190A is required for appropriate primary cilium formation in renal nephrons. P190A specifically localizes to the base of the cilia to permit axoneme elongation, which requires a functional GAP domain. Pharmacological manipulations further reveal that inhibition of either Rho kinase (ROCK) or F-actin polymerization is able to rescue the ciliogenesis defects observed upon loss of p190A activity. We propose a model in which p190A acts as a modulator of Rho GTPases in a localized area around the cilia to permit the dynamic actin rearrangement required for cilia elongation. Together, our results establish an unexpected link between Rho GTPase regulation, ciliogenesis and glomerulocystic kidney disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Point Mutation in p190A RhoGAP Affects Ciliogenesis and Leads to Glomerulocystic Kidney Defects

et al. 2016

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“…Cilia are particularly important to ensure correct Shh signaling during embryonic 38 development (Goetz and Anderson, 2010;He et al, 2017). Defects in cilia are linked to many human 39 diseases, known collectively as ciliopathies, including developmental disorders, neurodegeneration 40 and metabolic diseases (Reiter and Leroux, 2017;Yee and Reiter, 2015). 41…”

Section: Introduction 29mentioning

confidence: 99%

“…The pre-ciliary vesicles fuse and then surround the mother centriole concomitant with the 43 assembly of a series of protein modules that form a diffusion barrier separating the distal end of the 44 mother centriole from the rest of the cell cytoplasm (Garcia-Gonzalo et al, 2011). A microtubule 45 bundle, the axoneme, then extends from the centriole to allow cargo transport by the process of 46 intraflagellar transport (IFT) (Yee and Reiter, 2015). A "transition zone" (TZ) that separates the 47 mother centriole from the main length of the axoneme forms a diffusion barrier for both soluble and 48 membrane proteins at the base of the cilium (Garcia-Gonzalo et al, 2011; Garcia-Gonzalo and Reiter, 49 2017).…”

Section: Introduction 29mentioning

confidence: 99%

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Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function

Vuolo

Stevenson

Heesom

et al. 2018

Preprint

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The dynein-2 microtubule motor is the retrograde motor for intraflagellar transport. Mutations in dynein-2 components cause skeletal ciliopathies, notably Jeune syndrome. Dynein-2 comprises a heterodimer of two non-identical intermediate chains, WDR34 and WDR60. Here, we use knockout cell lines to demonstrate that each intermediate chain has a distinct role in cilia function. Both proteins are required to maintain a functional transition zone and for efficient bidirectional intraflagellar transport, only WDR34 is essential for axoneme extension. In contrast, only WDR60 is essential for co-assembly of the other subunits. Furthermore, WDR60 cannot compensate for loss of WDR34 or vice versa. This work defines a functional asymmetry to match the subunit asymmetry within the dynein-2 motor. Analysis of causative point mutations in WDR34 and WDR60 can partially restore function to knockout cells. Our data show that Jeune syndrome is caused by defects in transition zone architecture as well as intraflagellar transport.SUMMARYHere, Vuolo and colleagues use engineered knockout human cell lines to define roles for dynein-2 intermediate chains. WDR34 is required for axoneme extension, while WDR60 is not. Both subunits are required for cilia transition zone organization and bidirectional intraflagellar transport.

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Routes and machinery of primary cilium biogenesis

Bernabé‐Rubio

Alonso

2017

Cell. Mol. Life Sci.

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Primary cilia are solitary, microtubule-based protrusions of the cell surface that play fundamental roles as photosensors, mechanosensors and biochemical sensors. Primary cilia dysfunction results in a long list of developmental and degenerative disorders that combine to give rise to a large spectrum of human diseases affecting almost any major body organ. Depending on the cell type, primary ciliogenesis is initiated intracellularly, as in fibroblasts, or at the cell surface, as in renal polarized epithelial cells. In this review, we have focused on the routes of primary ciliogenesis placing particular emphasis on the recently described pathway in renal polarized epithelial cells by which the midbody remnant resulting from a previous cell division event enables the centrosome for initiation of primary cilium assembly. The protein machinery implicated in primary cilium formation in epithelial cells, including the machinery best known for its involvement in establishing cell polarity and polarized membrane trafficking, is also discussed.

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Ciliary Vesicle Formation: A Prelude to Ciliogenesis

Cited by 17 publications

References 11 publications

A Point Mutation in p190A RhoGAP Affects Ciliogenesis and Leads to Glomerulocystic Kidney Defects

A Point Mutation in p190A RhoGAP Affects Ciliogenesis and Leads to Glomerulocystic Kidney Defects

Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function

Routes and machinery of primary cilium biogenesis

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