Sdc2 and Tbx16 regulate Fgf2-dependent epithelial cell morphogenesis in the ciliated organ of asymmetry.

Heparan sulfate proteoglycans (HSPGs) control many cellular processes and have been implicated in the regulation of left-right (LR) development by as yet unknown mechanisms. Using lineage-targeted knockdowns, we found that the transmembrane HSPG Syndecan 2 (Sdc2) regulates LR patterning through cell-autonomous functions in the zebrafish ciliated organ of asymmetry, Kupffer's vesicle (KV), including regulation of cell proliferation and adhesion, cilia length and asymmetric fluid flow. Exploring downstream pathways, we found that the cell signaling ligand Fgf2 is exclusively expressed in KV cell lineages, and is dependent on Sdc2 and the transcription factor Tbx16. Strikingly, Fgf2 controls KV morphogenesis but not KV cilia length, and KV morphogenesis in sdc2 morphants can be rescued by expression of fgf2 mRNA. Through an Fgf2-independent pathway, Sdc2 and Tbx16 also control KV ciliogenesis. Our results uncover a novel Sdc2-Tbx16-Fgf2 pathway that regulates epithelial cell morphogenesis.