Reduced Fgf signaling during early zebrafish development causes ciliopathy-associated phenotypes

FGF signaling is used reiteratively during development and elicits several different responses, such as cell proliferation, differentiation, or migration. We parsed the complex FGF intracellular response by creating triple homozygous mutants in the Pea3 subgroup of ETS transcription factors, designated 3etv mutants. The Pea3 proteins Etv4 and Etv5 are expressed in areas of FGF activity; however, their role in FGF signal transduction as either positive or negative modulators of FGF activity was unclear. Using 3etv mutants, we found these genes act redundantly and have phenotypes consistent with known FGF defects in inner ear, pectoral fin, and posterior mesoderm development. Additionally, we uncovered a novel role for the FGF/Pea3 pathway during body axis straightening. 3etv larvae develop a curly-tail up (CTU) phenotype that we linked to mis-regulation of the polycystin and urotensin pathways, which have opposing actions to ensure a straight body orientation along the dorsal-ventral axis. We find that the Etv4/5 transcription factors act as positive regulators of FGF signaling and propose a model where Etv4/5 are required for cilia function downstream of Fgf8a. Summary StatementPea3 transcription factor triple mutants reveal a role for FGF signaling in balancing polycystin and urotensin signaling to achieve a straight body axis.