title: Multicilin drives centriole biogenesis via E2f proteins.
abstract: Multiciliate cells employ hundreds of motile cilia to produce fluid flow, which they nucleate and extend by first assembling hundreds of centrioles. In most cells, entry into the cell cycle allows centrioles to undergo a single round of duplication, but in differentiating multiciliate cells, massive centriole assembly occurs in G0 by a process initiated by a small coiled-coil protein, Multicilin. Here we show that Multicilin acts by forming a ternary complex with E2f4 or E2f5 and Dp1 that binds and activates most of the genes required for centriole biogenesis, while other cell cycle genes remain off. This complex also promotes the deuterosome pathway of centriole biogenesis by activating the expression of deup1 but not its paralog, cep63. Finally, we show that this complex is disabled by mutations in human Multicilin that cause a severe congenital mucociliary clearance disorder due to reduced generation of multiple cilia. By coopting the E2f regulation of cell cycle genes, Multicilin drives massive centriole assembly in epithelial progenitors in a manner required for multiciliate cell differentiation.
authors.affiliation: The Salk Institute for Biological Studies, La Jolla 92037, California, USA;
authors.forename: Lina
authors.initials: L
authors.lastname: Ma
authors.affiliation: The Salk Institute for Biological Studies, La Jolla 92037, California, USA;
authors.forename: Ian
authors.initials: I
authors.lastname: Quigley
authors.affiliation: Department of Pediatrics, University Hospital Muenster, 48149 Muenster; Germany.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.affiliation: The Salk Institute for Biological Studies, La Jolla 92037, California, USA;
authors.forename: Chris
authors.initials: C
authors.lastname: Kintner
mesh_terms: D000818:Animals; D002502:Centrioles / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000378:metabolism; D050680:Transcription Factor DP1 / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism
chemical_list: D050684:E2F Transcription Factors; D050680:Transcription Factor DP1; D029867:Xenopus Proteins; C571015:multicilin, Xenopus
keywords: centrioles; e2f4; multiciliate cells