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

Morphogen gradients pattern tissues by inducing dose-dependent transcriptional responses, yet cells that produce a morphogen often respond differently from their neighbors. Using the migrating zebrafish lateral line primordium as a tractable in vivo model of organogenesis, we uncover a cell autonomous role for the classical paracrine ligand Fgf3. Transcriptomic profiling and quantitative single-molecule imaging reveal an unexpected class of target genes, including the chemokine scavenger cxcr7b, whose expression decreases both when FGF receptor signaling is blocked and when Fgf3 is overexpressed. High-resolution live imaging shows that Fgf3 accumulates in the nucleus of ligand-producing cells while neighboring cells receive only extracellular ligand. Whole-embryo imaging reveals that this patterning feature is widespread across developing tissues. Mosaic gain-of-function, secretion-defective mutants, and nanobody-directed degradation demonstrate that the nuclear pool of Fgf3 autonomously represses related targets without impairing canonical receptor signaling. Structure-guided comparative trafficking assays suggest that nuclear targeting is a latent property shared by several paracrine FGFs. Together, these findings reveal a morphogen-intrinsic symmetry-breaking mechanism. Secreted Fgf3 activates generic target genes across the field and nuclear Fgf3 selectively silences a subset within source cells, hard-wiring differential responses between signal senders and receivers. We propose that dual secreted-nuclear functionality of FGF ligands may be a general strategy for patterning gene-expression during organogenesis.