XB-ART-39229Nature April 2, 2009; 458 (7238): 651-4.
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.
PubMed ID: 19242413
PMC ID: PMC2688717
Article link: Nature
Genes referenced: ace dnah9 dnai1 fgf8 fgfr1 foxj1 foxj1.2 ift88 prkci rfx2 sox17a
Article Images: [+] show captions
|Figure 4. FGF signaling controls ciliogenic genes in DFC/KV cells(a, b) sox17 expression in DFC/KV (and endoderm cells in a different focal plane) in 90% epiboly embryos was normal in fgfr1 morphants and WT embryos. (c, d) Expression of dnah9 in 95 % epiboly embryos was normal in fgfr1 morphants and WT embryos. (e, f) In contrast, foxJ1 was down-regulated in fgfr1 morphants versus WT embryos at 90% epiboly. (g, h) Similarly, polaris was down-regulated in fgfr1 morphants versus WT embryos at tailbud stage. (i) Comparison of percentage of embryos with WT expression levels of each gene indicated. (j) Proposed mechanism by which FGF signaling controls length of motile cilia: FGF ligands bind to FGFR1 activating downstream transcription factors (TF) including foxj1 and rfx2, these TF activate IFT genes (e.g. polaris) to maintain motile cilia length on epithelial cells.|