title: FGF signalling during embryo development regulates cilia length in diverse epithelia.
abstract: Cilia are cell surface organelles found on most epithelia in vertebrates. Specialized groups of cilia have critical roles in embryonic development, including left-right axis formation. Recently, cilia have been implicated as recipients of cell-cell signalling. However, little is known about cell-cell signalling pathways that control the length of cilia. Here we provide several lines of evidence showing that fibroblast growth factor (FGF) signalling regulates cilia length and function in diverse epithelia during zebrafish and Xenopus development. Morpholino knockdown of FGF receptor 1 (Fgfr1) in zebrafish cell-autonomously reduces cilia length in Kupffer's vesicle and perturbs directional fluid flow required for left-right patterning of the embryo. Expression of a dominant-negative FGF receptor (DN-Fgfr1), treatment with SU5402 (a pharmacological inhibitor of FGF signalling) or genetic and morpholino reduction of redundant FGF ligands Fgf8 and Fgf24 reproduces this cilia length phenotype. Knockdown of Fgfr1 also results in shorter tethering cilia in the otic vesicle and shorter motile cilia in the pronephric ducts. In Xenopus, expression of a dn-fgfr1 results in shorter monocilia in the gastrocoel roof plate that control left-right patterning and in shorter multicilia in external mucociliary epithelium. Together, these results indicate a fundamental and highly conserved role for FGF signalling in the regulation of cilia length in multiple tissues. Abrogation of Fgfr1 signalling downregulates expression of two ciliogenic transcription factors, foxj1 and rfx2, and of the intraflagellar transport gene ift88 (also known as polaris), indicating that FGF signalling mediates cilia length through an Fgf8/Fgf24-Fgfr1-intraflagellar transport pathway. We propose that a subset of developmental defects and diseases ascribed to FGF signalling are due in part to loss of cilia function.
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Eccles Institute of Human Genetics, Building 533, Room 3160, 15 North 2030 East, Salt Lake City, Utah 84112-5330, USA.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Neugebauer
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Amack
authors.forename: Annita G
authors.initials: AG
authors.lastname: Peterson
authors.forename: Brent W
authors.initials: BW
authors.lastname: Bisgrove
authors.forename: H Joseph
authors.initials: HJ
authors.lastname: Yost
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology; D002923:Cilia / Q000502:physiology*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000196:embryology* / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014982:Xenopus laevis / Q000196:embryology* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism
chemical_list: D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1