Fig. 5

FGFs involved in axonal development and function. A Schematic representation of the FGFs/FGFRs that play important roles in axon specification, extension and guidance. In dorsal root ganglia neurons, FGF2 promotes axon outgrowth and branching through activation of FGFR1. In hippocampal neurons, the FGF2 branching activity involves the expression of the MT-severing proteins katanin and spastin that cut bundled MTs into shorter fragments to allow their entry into the axonal filopodia where the new branch will arise. FGF4, FGF5, FGF7, and FGF8 enhance axonal branching in hippocampal granule neurons. The FGF4-mediated axonal branching requires the participation of the extracellular protein neuritin that promotes the recruitment of FGFR1 to the axonal surface. Besides its axon branching activities, FGF8 also promotes axon outgrowth of cochlear spiral ganglion neurons. In the growth cones, FGF13 acts as an MSP, whose interaction with MTs is essential for regulating axonal specification. A subset of FGFs can also provide chemotrophic cues for growth cones. FGF3, FGF8 and FGF10 act as attractive cues, while FGF2 has a chemorepulsive effect on growth cones. At higher concentrations FGF10 shifts its chemoattractant function to repellant activity. B FGFs are key in driving presynaptic formation while also playing an important role in the regulation of voltage-gated channels and, consequently, modulating the generation of action potentials. FGF2 acts on presynaptic terminals to induce clustering of synaptic vesicles, namely synaptotagmin, synapsin I and synaptophysin, in Xenopus spinal cord neurons and rat hippocampal neurons. Other FGF family members, such as FGF7, FGF10 and FGF22 are expressed in myotubes and act on motor neurons nerve terminals through FGFR2b to induce clustering of synapsin I and SV2 synaptic vesicles. In addition to their role in neuromuscular junction formation, FGF7 and FGF22 are crucial inhibitory and excitatory presynaptic organizers in hippocampal neurons, respectively. While FGF22 signals through FGFR1b and FGFR2b to induce presynaptic differentiation, FGF7 only activates FGFR2b. A subset of intracellular, non-secreted FGFs play important roles in the regulation of voltage-gated channels in the AIS, which are important for proper action potential generation. FGF14 and FGF12 both regulate Nav_1.2 channels, a highly expressed type of Nav channels in the AIS, the latter through a CAMKII-dependent mechanism. FGF14 regulates the localization and currents of Nav and KCNQ channels in the AIS, while also regulating presynaptic Cav_2.1 and Cav_2.2 channels. CAMKII, calmodulin-dependent protein kinase II; KCNQ, Kv channels; MSP, microtubule-stabilizing protein; MTs, microtubules