title: The ciliary GTPase Arl13b regulates cell migration and cell cycle progression.
abstract: The GTPase ARL13B is localized to primary cilia; small cellular protrusions that act as antennae. Its defective ARL13B hennin (HNN) variant is linked causally with Joubert Syndrome, a developmental ciliopathy attributed to poor sensing of extracellular chemical gradients. We tested the hypothesis that impaired detection of extracellular voltage gradients also contributes to the HNN phenotype. In vitro, extracellular electric fields stimulated migration of wild type (WT) and HNN fibroblasts toward the cathode but the field only increased the migration speed of WT cells. Cilia on WT cells did not align to the field vector. HNN cells divided more slowly than WT cells, arresting at the G2/M phase. Mechanistically, HNN cells had reduced phospho-ERK1/2 signaling and elevated levels of Suppressor of Fused protein. These suggest that cells may not be able to read extracellular chemical cues appropriately, resulting in deficits in cell migration and proliferation. Finally, an increase in tubulin stabilization (more detyrosinated tubulin) confirmed the general stagnation of HNN cells, which may further contribute to slower migration and cell cycle progression. We conclude that Arl13b dysfunction resulted in HNN cell stagnation due to poor growth factor signaling and impaired detection of extracellular electrical gradients, and that the role of Arl13b in cell proliferation may be understated.
authors.affiliation: a Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, and Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine , Shanghai , China.|b School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill , Aberdeen , Scotland , UK.
authors.forename: Michal
authors.initials: M
authors.lastname: Pruski
authors.affiliation: b School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill , Aberdeen , Scotland , UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Rajnicek
authors.affiliation: c Department of Pharmacy , Xijing Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Yang
authors.affiliation: b School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill , Aberdeen , Scotland , UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Clancy
authors.affiliation: a Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, and Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine , Shanghai , China.|b School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill , Aberdeen , Scotland , UK.
authors.forename: Yu-Qiang
authors.initials: YQ
authors.lastname: Ding
authors.affiliation: b School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill , Aberdeen , Scotland , UK.
authors.forename: Colin D
authors.initials: CD
authors.lastname: McCaig
authors.affiliation: b School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill , Aberdeen , Scotland , UK.
authors.forename: Bing
authors.initials: B
authors.lastname: Lang
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002923:Cilia / Q000378:metabolism*; D004560:Electricity; D004566:Electrodes; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016195:G2 Phase; D007150:Immunohistochemistry; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D008954:Models, Biological; D012097:Repressor Proteins; D016196:S Phase; D014404:Tubulin / Q000378:metabolism
chemical_list: C560093:Arl13b protein, mouse; D012097:Repressor Proteins; C490763:Sufu protein, mouse; D014404:Tubulin; D048049:Extracellular Signal-Regulated MAP Kinases; D020727:ADP-Ribosylation Factors
keywords: Arl13b; HNN; cell cycle; ciliopathies; migration; primary cilium