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

Abstract

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.