Nuclear rerouting of paracrine Fgf3 in source cells represses target genes to pattern morphogen responses

Morphogen gradients direct tissue patterning by inducing dose dependent transcriptional responses, yet ligand producing cells often respond differently from their neighbors. Using the zebrafish lateral line organogenesis model, we uncover a cell autonomous role for the paracrine ligand Fgf3. Transcriptomic profiling and quantitative single molecule imaging identify target genes, including the chemokine scavenger cxcr7b, whose expression decreases both when FGF receptor signaling is inhibited and when Fgf3 is overexpressed. High resolution live imaging reveals nuclear accumulation of Fgf3 in producing cells, whereas neighbors receive only extracellular ligand, a feature also observed in other embryonic tissues. Mosaic gain of function and nanobody mediated degradation demonstrate that the nuclear pool of Fgf3 autonomously represses specific targets without impairing canonical receptor signaling. Structure guided comparative assays indicate nuclear targeting as a latent property of several paracrine FGFs. Dual secreted nuclear functionality of FGF ligands may represent an intrinsic symmetry breaking mechanism during organogenesis.