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FGF signalling during embryo development regulates cilia length in diverse epithelia

Nature volume 458, pages 651–654 (2009)Cite this article

A Corrigendum to this article was published on 21 January 2010

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 signalling1,2. However, little is known about cell–cell signalling pathways that control the length of cilia3. 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 patterning4 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.

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Figure 1: Cell autonomous FGF signalling in Kupffer’s vesicle controls left–right patterning.
Figure 2: FGF signalling controls cilia length and directional fluid flow in Kupffer’s vesicle.
Figure 3: Cilia length in pronephric ducts, otic vesicles, gastrocoel roof plate epithelia and mucociliary epithelia is controlled by FGF signalling.
Figure 4: FGF signalling controls ciliogenic genes in zebrafish DFC/KV cells.

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Acknowledgements

We thank A. Moon and M. Condic for critical discussions on the manuscript; M. Karthikeyan, J. Shen, D. Coombs and E. Martini for technical help; and S. Miyagawa-Tomita, K. Poss and H. Issacs for reagents. This work was supported by American Heart Association predoctoral fellowship to J.M.N., NRSA Postdoctoral fellowship to J.D.A. and grants from NHLBI, NICHD and Primary Children’s Medical Foundation to H.J.Y.

Author Contributions J.M.N. performed all zebrafish experiments except KV flow analysis (by J.D.A.) and Xenopus experiments (by A.G.P.). B.W.B. cloned zebrafish foxj1, rfx2 and ift88. J.M.N. and H.J.Y. wrote the manuscript with input from all co-authors.

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  1. Jeffrey D. Amack

    Present address: Present address: Department of Cell and Developmental Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.,

Authors and Affiliations

  1. 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,

    Judith M. Neugebauer, Jeffrey D. Amack, Annita G. Peterson, Brent W. Bisgrove & H. Joseph Yost

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Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-7 with Legends (PDF 478 kb)

Supplementary Movie 1

This movie shows a dorsal view of the tailbud of a live Control morphants injected with fluorescent beads at 6-8 SS. DIC shows position of KV relative to the midline (notochord). Fluorescent imaging shows a counterclockwise flow of beads within KV, with an average bead velocity of 11.26 µM/sec (39 beads, 8 embryos). The green line circumscribes the KV. (MOV 9779 kb)

Supplementary Movie 2

This movie shows a dorsal view of the tailbud of a live fgfr1 morphant injected with fluorescent beads at 6-8 SS. DIC shows position of KV relative to the midline (notochord). Fluorescent imaging shows no persistent directional flow of beads, and a significantly reduced absolute velocity of 5.23 µM/sec (44 beads, 9 embryos). The green line circumscribes the KV. (MOV 10648 kb)

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Neugebauer, J., Amack, J., Peterson, A. et al. FGF signalling during embryo development regulates cilia length in diverse epithelia. Nature 458, 651–654 (2009). https://doi.org/10.1038/nature07753

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