title: The Rac1 regulator ELMO controls basal body migration and docking in multiciliated cells through interaction with Ezrin.
abstract: Cilia are microtubule-based organelles that are present on most cells and are required for normal tissue development and function. Defective cilia cause complex syndromes with multiple organ manifestations termed ciliopathies. A crucial step during ciliogenesis in multiciliated cells (MCCs) is the association of future basal bodies with the apical plasma membrane, followed by their correct spacing and planar orientation. Here, we report a novel role for ELMO-DOCK1, which is a bipartite guanine nucleotide exchange factor complex for the small GTPase Rac1, and for the membrane-cytoskeletal linker Ezrin, in regulating centriole/basal body migration, docking and spacing. Downregulation of each component results in ciliopathy-related phenotypes in zebrafish and disrupted ciliogenesis in Xenopus epidermal MCCs. Subcellular analysis revealed a striking impairment of basal body docking and spacing, which is likely to account for the observed phenotypes. These results are substantiated by showing a genetic interaction between elmo1 and ezrin b. Finally, we provide biochemical evidence that the ELMO-DOCK1-Rac1 complex influences Ezrin phosphorylation and thereby probably serves as an important molecular switch. Collectively, we demonstrate that the ELMO-Ezrin complex orchestrates ciliary basal body migration, docking and positioning in vivo.
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Epting
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Krasimir
authors.initials: K
authors.lastname: Slanchev
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Boehlke
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hoff
authors.affiliation: Department of General Pediatrics, University Children's Hospital Münster, Münster 48149, Germany.
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yasunaga
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Lara
authors.initials: L
authors.lastname: Indorf
authors.affiliation: Department of Anatomy and Cell Biology, University of Freiburg, Freiburg 79104, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Nestel
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg 79108, Germany.
authors.forename: Soeren S
authors.initials: SS
authors.lastname: Lienkamp
authors.affiliation: Department of General Pediatrics, University Children's Hospital Münster, Münster 48149, Germany.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg 79108, Germany.
authors.forename: E Wolfgang
authors.initials: EW
authors.lastname: Kuehn
authors.affiliation: BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg 79108, Germany Department of Computer Science, University of Freiburg, Freiburg 79110, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ronneberger
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg 79108, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg 79106, Germany albrecht.kramer-zucker@uniklinik-freiburg.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Kramer-Zucker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D054468:Axoneme / Q000378:metabolism / Q000648:ultrastructure; D064652:Basal Bodies / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002923:Cilia / Q000378:metabolism* / Q000648:ultrastructure; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000378:metabolism*; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000099149:Ezrin; C099818:DOCK1 protein, human; C071058:moesin; C071776:radixin
keywords: Ciliogenesis; DOCK1; ELMO; Ezrin; Multiciliated cells; Rac1; Xenopus; Zebrafish