Fibroblast Growth Factor Signalling in the Diseased Nervous System

Abstract

Fibroblast growth factors (FGFs) act as key signalling molecules in brain development, maintenance, and repair. They influence the intricate relationship between myelinating cells and axons as well as the association of astrocytic and microglial processes with neuronal perikarya and synapses. Advances in molecular genetics and imaging techniques have allowed novel insights into FGF signalling in recent years. Conditional mouse mutants have revealed the functional significance of neuronal and glial FGF receptors, not only in tissue protection, axon regeneration, and glial proliferation but also in instant behavioural changes. This review provides a summary of recent findings regarding the role of FGFs and their receptors in the nervous system and in the pathogenesis of major neurological and psychiatric disorders.

Keywords: Anxiety; Brain; CNS; Degeneration; Demyelination; Depression; FGF; FGFR; Ganglia; Glioma; Nerve; PNS; Receptor; Regeneration; Remyelination; Schizophrenia; Spinal cord.

Fig. 1

The neuronal FGFR signalling network, from the binding of ligands to downstream events. FGFR1-3 monomers (1) form homodimers (2) and heterodimers (3) either in a ligand-dependent (2, 3) or independent (4) mode. The latter may undergo autophosphorylation. FGF ligand binding leads to enhanced receptor phosphorylation. The ordered and cooperative post-translational modifications are depicted as an activation code with sequentially phosphorylated tyrosine residues (boxed inset, 4). Certain downstream pathways like PLCγ and STAT3 require specific phosphorylation of additional tyrosine residues. Phosphorylation activates downstream pathways such as PLCγ, AKT, ERK, and STAT3. These are regulated by a number of proteins that provide an inhibitory feedback, thereby limiting activation (SPRY, Sef, and DUSP6; depicted in red). The lipid-anchored fibroblast growth factor receptor substrate 2 (FRS2) undergoes phosphorylation by FGFR kinase activity and recruits downstream factors PI3K and Ras/ERK as signalling hubs. However, this mechanism is FGFR-specific, with FGFR1 showing higher activity than the other FGFRs (boxed inset). Moreover, FGFR subtypes differentially activate downstream ERK and PLCγ with FGFR1 showing stronger activation than FGFR2 or FGFR4, respectively (boxed inset). For references, see text

Fig. 2

Key mechanisms of FGF/FGFRs in the nervous system. The central nervous system comprises a large number of functionally and structurally diverse neuronal and glial cell types. The figure depicts model neurons forming synaptic connections as well as oligodendrocytes, astrocytes, and microglia. Modulation of synaptic connections by FGFs (boxed inset): FGF22 regulates the formation of excitatory synapses together with FGFR1b and R2b. Although both are involved in excitatory synapse regulation, inhibitory synapses are regulated by FGF7 via FGFR2b only. FGF2 and 20 synergise to regulate differentiation of dopaminergic neurons by using FGFR1IIIc as the receptor (FGF20 also binds to FGFR1IIIc in other neurons). When secreted by neurons, FGF2 enhances microglia activation, leading to increased removal of neuronal debris in case of neuronal damage. Moreover, FGF2 restores spatial learning, long-term potentiation, and neurogenesis in Alzheimer´s disease. Mechanistically, FGFR1 regulates CD200, which in turn mediates microglia responses and neurite outgrowth. This factor also feeds back by activation of FGFR1. Axonal growth and regeneration is stimulated mainly by FGF1 and FGF2. FGF2 secreted by neurons stimulates astrocytes via FGFR1-3 activation. Signalling from astrocytes to oligodendrocytes is accomplished by FGF2 influencing the survival and proliferation of oligodendrocyte precursor cells (OPCs). FGFR1 and R2 regulate myelin thickness and gene expression. For references, see text