title: Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport.
abstract: Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood. Here we report that prostaglandin signalling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants show ciliogenesis defects, and the lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4(T804M) mutant. PGE2 synthesis enzyme cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates the cyclic-AMP-mediated signalling cascade, are required for cilium formation and elongation. Importantly, PGE2 signalling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signalling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis.
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Genetics, Fudan University School of Life Sciences, Shanghai 200433, China.
authors.forename: Daqing
authors.initials: D
authors.lastname: Jin
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Tennessee 37232, USA.
authors.forename: Terri T
authors.initials: TT
authors.lastname: Ni
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Genetics, Fudan University School of Life Sciences, Shanghai 200433, China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Tennessee 37232, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wan
authors.affiliation: Department of Cell &Developmental Biology, State University of New York Upstate Medical University, New York 13210, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Amack
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Genetics, Fudan University School of Life Sciences, Shanghai 200433, China.
authors.forename: Guangju
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Cell &Developmental Biology, Vanderbilt University School of Medicine, Tennessee 37232, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fleming
authors.affiliation: Department of Cell &Developmental Biology, Vanderbilt University School of Medicine, Tennessee 37232, USA.
authors.forename: Chin
authors.initials: C
authors.lastname: Chiang
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Genetics, Fudan University School of Life Sciences, Shanghai 200433, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics, The University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Papierniak
authors.affiliation: Department of Pharmaceutical Science, St Jude Children's Research Hospital, Tennessee 38163, USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Cheepala
authors.affiliation: Division of Cancer Biology and Genetics, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Conseil
authors.affiliation: Division of Cancer Biology and Genetics, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Susan P C
authors.initials: SP
authors.lastname: Cole
authors.affiliation: Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02148, USA.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Drummond
authors.affiliation: Department of Pharmaceutical Science, St Jude Children's Research Hospital, Tennessee 38163, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics, The University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Jarema
authors.initials: J
authors.lastname: Malicki
authors.affiliation: 1] State Key Laboratory of Genetic Engineering, Department of Genetics, Fudan University School of Life Sciences, Shanghai 200433, China [2] Department of Medicine, Vanderbilt University School of Medicine, Tennessee 37232, USA.
authors.forename: Tao P
authors.initials: TP
authors.lastname: Zhong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002923:Cilia / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015232:Dinoprostone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D058309:Receptors, Prostaglandin E, EP4 Subtype; D029961:Zebrafish Proteins; C000592651:Abcc4 protein, zebrafish