title: Bbs8, together with the planar cell polarity protein Vangl2, is required to establish left-right asymmetry in zebrafish.
abstract: Laterality defects such as situs inversus are not uncommonly encountered in humans, either in isolation or as part of another syndrome, but can have devastating developmental consequences. The events that break symmetry during early embryogenesis are highly conserved amongst vertebrates and involve the establishment of unidirectional flow by cilia within an organising centre such as the node in mammals or Kupffer's vesicle (KV) in teleosts. Disruption of this flow can lead to the failure to successfully establish left-right asymmetry. The correct apical-posterior cellular position of each node/KV cilium is critical for its optimal radial movement which serves to sweep fluid (and morphogens) in the same direction as its neighbours. Planar cell polarity (PCP) is an important conserved process that governs ciliary position and posterior tilt; however the underlying mechanism by which this occurs remains unclear. Here we show that Bbs8, a ciliary/basal body protein important for intraciliary/flagellar transport and the core PCP protein Vangl2 interact and are required for establishment and maintenance of left-right asymmetry during early embryogenesis in zebrafish. We discovered that loss of bbs8 and vangl2 results in laterality defects due to cilia disruption at the KV. We showed that perturbation of cell polarity following abrogation of vangl2 causes nuclear mislocalisation, implying defective centrosome/basal body migration and apical docking. Moreover, upon loss of bbs8 and vangl2, we observed defective actin organisation. These data suggest that bbs8 and vangl2 act synergistically on cell polarization to establish and maintain the appropriate length and number of cilia in the KV and thereby facilitate correct LR asymmetry.
authors.affiliation: Molecular Medicine Unit, Institute of Child Health, University College London, WC1N 1EH, UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: May-Simera
authors.forename: Masatake
authors.initials: M
authors.lastname: Kai
authors.forename: Victor
authors.initials: V
authors.lastname: Hernandez
authors.forename: Daniel P S
authors.initials: DP
authors.lastname: Osborn
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tada
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
mesh_terms: D000818:Animals; D019521:Body Patterning; D016764:Cell Polarity / Q000502:physiology*; D002923:Cilia / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D029961:Zebrafish Proteins; C552737:ttc8 protein, zebrafish; C491759:vangl2 protein, zebrafish