Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix

Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.

Auditory spatial acuity approximates the resolving power of space-specific neurons

The relationship between neuronal acuity and behavioral performance was assessed in the barn owl (Tyto alba), a nocturnal raptor renowned for its ability to localize sounds and for the topographic representation of auditory space found in the midbrain. We measured discrimination of sound-source separation using a newly developed procedure involving the habituation and recovery of the pupillary dilation response. The smallest discriminable change of source location was found to be about two times finer in azimuth than in elevation. Recordings from neurons in its midbrain space map revealed that their spatial tuning, like the spatial discrimination behavior, was also better in azimuth than in elevation by a factor of about two. Because the PDR behavioral assay is mediated by the same circuitry whether discrimination is assessed in azimuth or in elevation, this difference in vertical and horizontal acuity is likely to reflect a true difference in sensory resolution, without additional confounding effects of differences in motor performance in the two dimensions. Our results, therefore, are consistent with the hypothesis that the acuity of the midbrain space map determines auditory spatial discrimination.