title: Arl13b and the exocyst interact synergistically in ciliogenesis.
abstract: Arl13b belongs to the ADP-ribosylation factor family within the Ras superfamily of regulatory GTPases. Mutations in Arl13b cause Joubert syndrome, which is characterized by congenital cerebellar ataxia, hypotonia, oculomotor apraxia, and mental retardation. Arl13b is highly enriched in cilia and is required for ciliogenesis in multiple organs. Nevertheless, the precise role of Arl13b remains elusive. Here we report that the exocyst subunits Sec8, Exo70, and Sec5 bind preferentially to the GTP-bound form of Arl13b, consistent with the exocyst being an effector of Arl13b. Moreover, we show that Arl13b binds directly to Sec8 and Sec5. In zebrafish, depletion of arl13b or the exocyst subunit sec10 causes phenotypes characteristic of defective cilia, such as curly tail up, edema, and abnormal pronephric kidney development. We explored this further and found a synergistic genetic interaction between arl13b and sec10 morphants in cilia-dependent phenotypes. Through conditional deletion of Arl13b or Sec10 in mice, we found kidney cysts and decreased ciliogenesis in cells surrounding the cysts. Moreover, we observed a decrease in Arl13b expression in the kidneys from Sec10 conditional knockout mice. Taken together, our results indicate that Arl13b and the exocyst function together in the same pathway leading to functional cilia.
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal duarte.barral@nms.unl.pt cecilia.seixas@nms.unl.pt.
authors.forename: Cecília
authors.initials: C
authors.lastname: Seixas
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813.
authors.forename: Noemi
authors.initials: N
authors.lastname: Polgar
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30022.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Umberger
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30022.
authors.forename: Michael P
authors.initials: MP
authors.lastname: East
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zuo
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Moreiras
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, INSERM, UMR7258, 13009 Marseille, France.
authors.forename: Rania
authors.initials: R
authors.lastname: Ghossoub
authors.affiliation: INSERM UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benmerah
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30022.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kahn
authors.affiliation: Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813.
authors.forename: Ben
authors.initials: B
authors.lastname: Fogelgren
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30022.
authors.forename: Tamara
authors.initials: T
authors.lastname: Caspary
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425 Department of Medicine, RHJ Veterans Affairs Medical Center, Charleston, SC 29425.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Lipschutz
authors.affiliation: CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal duarte.barral@nms.unl.pt cecilia.seixas@nms.unl.pt.
authors.forename: Duarte C
authors.initials: DC
authors.lastname: Barral
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000015:Abnormalities, Multiple; D000818:Animals; D002531:Cerebellum / Q000002:abnormalities; D002923:Cilia / Q000378:metabolism*; D005124:Eye Abnormalities; D056726:Genetic Association Studies; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D052177:Kidney Diseases, Cystic; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D041681:NIH 3T3 Cells; D012160:Retina / Q000002:abnormalities; D033921:Vesicular Transport Proteins / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C560093:Arl13b protein, mouse; D033921:Vesicular Transport Proteins; D029961:Zebrafish Proteins; D020727:ADP-Ribosylation Factors; C530391:ARL13B protein, human; C545718:Arl13b protein, zebrafish