{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:41:09Z","timestamp":1792186869859,"version":"4.4.0"},"reference-count":51,"publisher":"The Company of Biologists","issue":"23","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,12,1]]},"abstract":"<jats:p>arl13b was initially cloned as the novel cystic kidney gene scorpion (sco) in zebrafish and was shown to be required for cilia formation in the kidney duct. In mouse, a null mutant of Arl13b shows abnormal ultrastructure of the cilium and defective sonic hedgehog (Shh) signaling. Importantly, a recent study linked mutations in ARL13B to a classical form of Joubert syndrome (JS), an autosomal recessive disorder characterized by a distinctive cerebellar malformation. In this study, we analyzed the zebrafish arl13b (sco) mutant and gene products in detail. We first demonstrate that Arl13b is a protein that is highly enriched in the cilium and is required for cilia formation in multiple organs in zebrafish, and that knockdown of arl13b leads to multiple cilia-associated phenotypes. We additionally show that multiple regions of Arl13b are required for its localization to the cilium. By means of rescuing experiments with a series of deletion and point mutants, we further demonstrate that the ciliary localization is crucial for the in vivo function of Arl13b. Together, these results strongly support the hypothesis that JS-related disease (JSRD) is a ciliopathy, or a disease caused by ciliary defects, and that Arl13b functions mainly through the cilium.<\/jats:p>","DOI":"10.1242\/dev.036350","type":"journal-article","created":{"date-parts":[[2009,11,11]],"date-time":"2009-11-11T17:48:03Z","timestamp":1257961683000},"page":"4033-4042","source":"Crossref","is-referenced-by-count":138,"title":["Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b\/Scorpion"],"prefix":"10.1242","volume":"136","author":[{"given":"Neil A.","family":"Duldulao","sequence":"first","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, 333 Cedar Street, NSB-393, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunjin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, 333 Cedar Street, NSB-393, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxia","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, 333 Cedar Street, NSB-393, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042605542438500_R1","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/j.cub.2009.04.053","article-title":"The extracellular domain of Smoothened regulates ciliary localization and is required for high-level Hh signaling","volume":"19","author":"Aanstad","year":"2009","journal-title":"Curr. Biol."},{"key":"2021042605542438500_R2","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/j.cell.2006.06.013","article-title":"Life without centrioles: cilia in the spotlight","volume":"125","author":"Badano","year":"2006","journal-title":"Cell"},{"key":"2021042605542438500_R3","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/ng.423","article-title":"Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies","volume":"9","author":"Bielas","year":"2009","journal-title":"Nat. Genet."},{"key":"2021042605542438500_R4","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ajhg.2008.06.023","article-title":"Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome","volume":"83","author":"Cantagrel","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"2021042605542438500_R5","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.devcel.2007.03.004","article-title":"The graded response to Sonic Hedgehog depends on cilia architecture","volume":"12","author":"Caspary","year":"2007","journal-title":"Dev. Cell"},{"key":"2021042605542438500_R6","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1136\/jmg.2004.027375","article-title":"NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders","volume":"42","author":"Castori","year":"2005","journal-title":"J. Med. Genet."},{"key":"2021042605542438500_R7","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1093\/hmg\/ddn384","article-title":"Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway","volume":"18","author":"DiBella","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2021042605542438500_R8","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1086\/425985","article-title":"Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria","volume":"75","author":"Dixon-Salazar","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"2021042605542438500_R9","doi-asserted-by":"crossref","first-page":"4655","DOI":"10.1242\/dev.125.23.4655","article-title":"Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function","volume":"125","author":"Drummond","year":"1998","journal-title":"Development"},{"key":"2021042605542438500_R10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/418037a","article-title":"Conserved function for embryonic nodal cilia","volume":"418","author":"Essner","year":"2002","journal-title":"Nature"},{"key":"2021042605542438500_R11","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1242\/dev.01663","article-title":"Kupffer's vesicle is a ciliated organ of asymmetry in the zebrafish embryo that initiates left-right development of the brain, heart and gut","volume":"132","author":"Essner","year":"2005","journal-title":"Development"},{"key":"2021042605542438500_R12","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1038\/ng1414","article-title":"Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome","volume":"36","author":"Fan","year":"2004","journal-title":"Nat. Genet."},{"key":"2021042605542438500_R13","doi-asserted-by":"crossref","first-page":"e4348","DOI":"10.1371\/journal.pone.0004348","article-title":"Rapid mutation of endogenous zebrafish genes using zinc finger nucleases made by Oligomerized Pool ENgineering (OPEN)","volume":"4","author":"Foley","year":"2009","journal-title":"PLoS ONE"},{"key":"2021042605542438500_R14","doi-asserted-by":"crossref","first-page":"3781","DOI":"10.1091\/mbc.e06-02-0133","article-title":"The intraflagellar transport protein IFT20 is associated with the Golgi complex and is required for cilia assembly","volume":"17","author":"Follit","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"2021042605542438500_R15","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1242\/jcs.02818","article-title":"Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif","volume":"119","author":"Geng","year":"2006","journal-title":"J. Cell Sci."},{"key":"2021042605542438500_R16","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/ng.2007.12","article-title":"Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response","volume":"39","author":"Gerdes","year":"2007","journal-title":"Nat. Genet."},{"key":"2021042605542438500_R17","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/ajmg.a.20437","article-title":"Molar tooth sign of the midbrain-hindbrain junction: occurrence in multiple distinct syndromes","volume":"125","author":"Gleeson","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042605542438500_R18","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/ng896","article-title":"Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development","volume":"31","author":"Golling","year":"2002","journal-title":"Nat. Genet."},{"key":"2021042605542438500_R19","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.ajhg.2008.10.002","article-title":"CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290","volume":"83","author":"Gorden","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"2021042605542438500_R20","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1038\/sj.ki.5002577","article-title":"Genetic complexity in Joubert syndrome and related disorders","volume":"72","author":"Harris","year":"2007","journal-title":"Kidney Int."},{"key":"2021042605542438500_R21","first-page":"139","article-title":"Multicolor whole-mount in situ hybridization","volume":"137","author":"Hauptmann","year":"2000","journal-title":"Methods Mol. Biol."},{"key":"2021042605542438500_R22","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1136\/jmg.2007.052027","article-title":"Mutation analysis of NPHP6\/CEP290 in patients with Joubert syndrome and Senior-Loken syndrome","volume":"44","author":"Helou","year":"2007","journal-title":"J. Med. Genet."},{"key":"2021042605542438500_R23","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.bbrc.2008.06.001","article-title":"Domain architecture of the atypical Arf-family GTPase Arl13b involved in cilia formation","volume":"373","author":"Hori","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021042605542438500_R24","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1242\/dev.041343","article-title":"Dampened Hedgehog signaling but normal Wnt signaling in zebrafish without cilia","volume":"136","author":"Huang","year":"2009","journal-title":"Development"},{"key":"2021042605542438500_R25","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/ng.427","article-title":"INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse","volume":"9","author":"Jacoby","year":"2009","journal-title":"Nat. Genet."},{"key":"2021042605542438500_R26","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.devcel.2008.03.010","article-title":"Cystic kidney gene seahorse regulates cilia-mediated processes and Wnt pathways","volume":"14","author":"Kishimoto","year":"2008","journal-title":"Dev. Cell"},{"key":"2021042605542438500_R27","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.bbrc.2009.02.087","article-title":"Biochemical characterization of missense mutations in the Arf\/Arl-family small GTPase Arl6 causing Bardet-Biedl syndrome","volume":"381","author":"Kobayashi","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021042605542438500_R28","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1242\/dev.01772","article-title":"Cilia-driven fluid flow in the zebrafish pronephros, brain and Kupffer's vesicle is required for normal organogenesis","volume":"132","author":"Kramer-Zucker","year":"2005","journal-title":"Development"},{"key":"2021042605542438500_R29","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.1002\/dvdy.21343","article-title":"The Tol2kit: a multisite gateway-based construction kit for Tol2 transposon transgenesis constructs","volume":"236","author":"Kwan","year":"2007","journal-title":"Dev. Dyn."},{"key":"2021042605542438500_R30","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/ng.97","article-title":"Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome","volume":"40","author":"Leitch","year":"2008","journal-title":"Nat. Genet."},{"key":"2021042605542438500_R31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-213X-6-1","article-title":"Proteomics of early zebrafish embryos","volume":"6","author":"Link","year":"2006","journal-title":"BMC Dev. Biol."},{"key":"2021042605542438500_R32","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1242\/dev.00436","article-title":"The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry","volume":"130","author":"Long","year":"2003","journal-title":"Development"},{"key":"2021042605542438500_R33","doi-asserted-by":"crossref","first-page":"4543","DOI":"10.1242\/jcs.114.24.4543","article-title":"Regulation of Golgi structure and function by ARF-like protein 1 (Arl1)","volume":"114","author":"Lu","year":"2001","journal-title":"J. Cell Sci."},{"key":"2021042605542438500_R34","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/nbt1398","article-title":"Targeted gene inactivation in zebrafish using engineered zinc-finger nucleases","volume":"26","author":"Meng","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"2021042605542438500_R35","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/79951","article-title":"Effective targeted gene \u2018knockdown\u2019 in zebrafish","volume":"26","author":"Nasevicius","year":"2000","journal-title":"Nat. Genet."},{"key":"2021042605542438500_R36","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.molbiopara.2004.01.009","article-title":"Sequences required for the flagellar targeting of an integral membrane protein","volume":"135","author":"Nasser","year":"2004","journal-title":"Mol. Biochem. Parasitol."},{"key":"2021042605542438500_R37","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1083\/jcb.200308132","article-title":"Intraflagellar transport (IFT) cargo: IFT transports flagellar precursors to the tip and turnover products to the cell body","volume":"164","author":"Qin","year":"2004","journal-title":"J. Cell Biol."},{"key":"2021042605542438500_R38","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/ng1644","article-title":"Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates","volume":"37","author":"Ross","year":"2005","journal-title":"Nat. Genet."},{"key":"2021042605542438500_R39","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/1526-968X(200008)27:4<159::AID-GENE50>3.0.CO;2-T","article-title":"Role of the zebrafish trilobite locus in gastrulation movements of convergence and extension","volume":"27","author":"Sepich","year":"2000","journal-title":"Genesis"},{"key":"2021042605542438500_R40","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0070-2153(08)00813-2","article-title":"Chapter 13 ciliary dysfunction in developmental abnormalities and diseases","volume":"85","author":"Sharma","year":"2008","journal-title":"Curr. Top Dev. Biol."},{"key":"2021042605542438500_R41","doi-asserted-by":"crossref","first-page":"29543","DOI":"10.1074\/jbc.274.41.29543","article-title":"Characterization of a targeting motif for a flagellar membrane protein in Leishmania enriettii","volume":"274","author":"Snapp","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021042605542438500_R42","doi-asserted-by":"crossref","first-page":"4085","DOI":"10.1242\/dev.01240","article-title":"A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney","volume":"131","author":"Sun","year":"2004","journal-title":"Development"},{"key":"2021042605542438500_R43","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1083\/jcb.151.7.1369","article-title":"Identification of an outer segment targeting signal in the COOH terminus of rhodopsin using transgenic Xenopus laevis","volume":"151","author":"Tam","year":"2000","journal-title":"J. Cell Biol."},{"key":"2021042605542438500_R44","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S0896-6273(04)00268-5","article-title":"Intraflagellar transport genes are essential for differentiation and survival of vertebrate sensory neurons","volume":"42","author":"Tsujikawa","year":"2004","journal-title":"Neuron"},{"key":"2021042605542438500_R45","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s00467-005-2054-y","article-title":"Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome","volume":"21","author":"Utsch","year":"2006","journal-title":"Pediatr. Nephrol."},{"key":"2021042605542438500_R46","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1681\/ASN.2006111282","article-title":"SIX2 and BMP4 mutations associate with anomalous kidney development","volume":"19","author":"Weber","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021042605542438500_R47","volume-title":"The Zebrafish Book: a guide for the laboratory use of zebrafish (Danio rerio)","author":"Westerfield","year":"2000"},{"key":"2021042605542438500_R48","first-page":"F420","article-title":"Reversed polarity of Na(+) -K(+) -ATPase: mislocation to apical plasma membranes in polycystic kidney disease epithelia","volume":"260","author":"Wilson","year":"1991","journal-title":"Am. J. Physiol."},{"key":"2021042605542438500_R49","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1371\/journal.pgen.0030189","article-title":"The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros","volume":"3","author":"Wingert","year":"2007","journal-title":"PLoS Genet."},{"key":"2021042605542438500_R50","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1038\/sj.ki.5002630","article-title":"Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis","volume":"72","author":"Wolf","year":"2007","journal-title":"Kidney Int."},{"key":"2021042605542438500_R51","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/gt.2009.16","article-title":"Progress and prospects: techniques for site-directed mutagenesis in animal models","volume":"5","author":"Yan","year":"2009","journal-title":"Gene Ther."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/136\/23\/4033\/1570352\/4033.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/136\/23\/4033\/1570352\/4033.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T07:25:31Z","timestamp":1619421931000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/136\/23\/4033\/43776\/Cilia-localization-is-essential-for-in-vivo"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12,1]]},"references-count":51,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2009,12,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.036350","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2009,12,1]]}}}