Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in <i>Caenorhabditis elegans</i>

Cevik, Sebiha; Hori, Yuichi; Kaplan, Oktay I.; Kaczyńska, Katarzyna; Toivenon, T; Foley-Fisher, C; Cottell, David C.; Katada, Toshiaki; Kontani, Kenji; Blacque, Oliver E.

doi:10.1083/jcb.200908133

Cited by 173 publications

(213 citation statements)

References 54 publications

(124 reference statements)

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“…11,12 Similarly, arl-13, the Caenorhabditis elegans orthologue of ARL13B, functions in ciliary membranes, where it is involved in ciliary transmembrane protein localization and transport of proteins to the tip of the cilium. 13,14 More recently, Arl13b signaling in primary cilia has been shown to be crucial for the polarization of radial glial scaffold, an essential step in cerebral cortex formation. 15 To validate the effect of this novel variant in vivo, we took advantage of the phenotypes observed in zebrafish arl13b sco mutants and in Arl13b hnn mouse embryonic fibroblasts (MEFs) and tested the ability of mutated human ARL13B to rescue these phenotypes.…”

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confidence: 99%

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

et al. 2014

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Joubert syndrome (JS) is a genetically heterogeneous autosomal recessive ciliopathy with 22 genes implicated to date, including a small, ciliary GTPase, ARL13B. ARL13B is required for cilia formation in vertebrates. JS patients display multiple symptoms characterized by ataxia due to the cerebellar vermis hypoplasia, and that can also include ocular abnormalities, renal cysts, liver fibrosis or polydactyly. These symptoms are shared with other ciliopathies, some of which display additional phenotypes, such as obesity. Here we identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient who displayed retinal defects and obesity. We demonstrate the variant disrupts ARL13B function, as its expression did not rescue the mutant phenotype either in Arl13b scorpion zebrafish or in Arl13b hennin mouse embryonic fibroblasts, while the wild-type ARL13B did. Finally, we show that ARL13B is localized within the primary cilia of neonatal mouse hypothalamic neurons consistent with the known link between hypothalamic ciliary function and obesity. Thus our data identify a novel ARL13B variant that causes JS and retinopathy and suggest an extension of the phenotypic spectrum of ARL13B mutations to obesity.

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confidence: 99%

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

et al. 2014

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“…Fluorescence miscroscopy and IFT transport assays were conducted as described previously (Cevik et al, 2010). For colocalisation and co-movement analysis, twocolour images or movies of fluorescent-tagged proteins (red and green) were captured with an iXon EM + DV885 EMCCD camera (Andor Technology), operating on a Nikon motorised inverted research microscope (Eclipse Ti-E), coupled to a spinning disk confocal head and green (488 nm) and red (561 nm) laser excitation.…”

Section: Elegans Fluorescence Microscopy and Ift Dendritic Compartmentioning

confidence: 99%

The AP-1 clathrin adaptor facilitates cilium formation and functions with RAB-8 in C. elegans ciliary membrane transport

Kaplan

Mollà-Herman

Cevik

et al. 2010

Journal of Cell Science

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SummaryClathrin adaptor (AP) complexes facilitate membrane trafficking between subcellular compartments. One such compartment is the cilium, whose dysfunction underlies disorders classified as ciliopathies. Although AP-1mu subunit (UNC-101) is linked to cilium formation and targeting of transmembrane proteins (ODR-10) to nematode sensory cilia at distal dendrite tips, these functions remain poorly understood. Here, using Caenorhabditis elegans sensory neurons and mammalian cell culture models, we find conservation of AP-1 function in facilitating cilium morphology, positioning and orientation, and microtubule stability and acetylation. These defects appear to be independent of IFT, because AP-1-depleted cells possess normal IFT protein localisation and motility. By contrast, disruption of chc-1 (clathrin) or rab-8 phenocopies unc-101 worms, preventing ODR-10 vesicle formation and causing misrouting of ODR-10 to all plasma membrane destinations. Finally, ODR-10 colocalises with RAB-8 in cell soma and they cotranslocate along dendrites, whereas ODR-10 and UNC-101 signals do not overlap. Together, these data implicate conserved roles for metazoan AP-1 in facilitating cilium structure and function, and suggest cooperation with RAB-8 to coordinate distinct early steps in neuronal ciliary membrane sorting and trafficking.

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“…84 ARL13 regulates the binding of IFT-A and IFT-B, while ARL3 acts antagonistically with ARL-13 to regulate IFT integrity and ciliogenesis. 68,85 Defects in Arl13 mutants are rescued by depletion of ARL3 through an HDAC6-dependent pathway suggesting that ARL13 acts antagonistically with ARL3 in cilia formation. 68 Like ARL3, activation of HDAC6 was also found to promote cilia disassembly while loss of HDAC6 activity selectively stabilizes cilia in human epithelial cells.…”

Section: Small Gtpases and Motor Proteins In Vesicle Traffickingmentioning

confidence: 98%

Role of small GTPases in polarized vesicle transport to primary cilium

Rao¹,

Khanna²

2015

RRB

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Small GTPases play crucial roles in regulating polarized vesicle trafficking in a cell. These molecules are involved in diverse pathways and regulate cell shape, organelle integrity, and cell signaling. One of the most important cellular signaling centers is the primary or sensory cilium. Small GTPases orchestrate a diverse set of events to not only generate these structures but also mediate their function and maintenance during the life of the cell. In this review, we will discuss the various small GTPases involved in regulating cilia biogenesis and function and their involvement in human diseases.

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Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans

Abstract: The small GTPase Arl13b regulates ciliary transmembrane protein localizations and anterograde IFT assembly stability.

Cited by 173 publications

References 54 publications

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

The AP-1 clathrin adaptor facilitates cilium formation and functions with RAB-8 in C. elegans ciliary membrane transport

Role of small GTPases in polarized vesicle transport to primary cilium

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