FGF Signaling during embryo development regulates cilia length in diverse epithelia

Cilia are cell surface organelles found on most epithelia in vertebrates. Specialized groups of cilia play critical roles in embryonic development, including left-right (LR) axis formation. Recently, cilia have been implicated as recipients of cell-cell signaling1, 2. However, little is known about cell-cell signaling pathways that control the length of cilia3. Here we provide several lines of evidence showing that fibroblast growth factor (FGF) signaling regulates cilia length and function in diverse epithelia during zebrafish and Xenopus development. Morpholino (MO) knockdown of FGF receptor 1 (FGFR1) in zebrafish cell-autonomously reduces cilia length in Kupffer’s vesicle (KV) and perturbs directional fluid flow required for LR patterning of the embryo. Expression of a dominant-negative FGFR (DN-FGFR), treatment with SU5402, a pharmacological inhibitor of FGF signaling, 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-FGFR results in shorter monocilia in the gastrocoel roof plate (GRP) that control LR patterning4 and in shorter multicilia in external mucociliary epithelium. Together, these results suggest a fundamental and highly conserved role for FGF signaling in the regulation of cilia length in multiple tissues. Abrogation of FGFR1 signaling down-regulates expression of two ciliogenic transcription factors, foxj1 and rfx2, and the intraflagellar transport (IFT) gene, polaris, suggesting that FGF signaling mediates cilia length through an FGF8/FGF24 - FGFR1- IFT pathway. We propose that a subset of developmental defects and diseases ascribed to FGF signaling are due in part to loss of cilia function.