Fibroblast growth factors and their receptors in the central nervous system

Abstract

Fibroblast growth factors (FGFs) and their receptors constitute an elaborate signaling system that participates in many developmental and repair processes of virtually all mammalian tissues. Among the 23 FGF members, ten have been identified in the brain. Four FGF receptors (FGFRs), receptor tyrosine kinases, are known so far. Ligand binding of these receptors greatly depends on the presence of heparan sulfate proteoglycans, which act as low affinity FGFRs. Ligand binding specificity of FGFRs depends on the third extracellular Ig-like domain, which is subject to alternative splicing. Activation of FGFRs triggers several intracellular signaling cascades. These include phosphorylation of src and PLCgamma leading finally to activation of PKC, as well as activation of Crk and Shc. SNT/FRS2 serves as an alternative link of FGFRs to the activation of PKC and, in addition, activates the Ras signaling cascade. In the CNS, FGFs are widely expressed; FGF-2 is predominantly synthesized by astrocytes, whereas other FGF family members, e.g., FGF-5, FGF-8, and FGF-9, are primarily synthesized by neurons. During CNS development FGFs play important roles in neurogenesis, axon growth, and differentiation. In addition, FGFs are major determinants of neuronal survival both during development and during adulthood. Adult neurogenesis depends greatly on FGF-2. Finally, FGF-1 and FGF-2 seem to be involved in the regulation of synaptic plasticity and processes attributed to learning and memory.

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

“…4A-4C). It has been shown previously that NPCs isolated from rat embryo cortex (E14.5) cultured in bFGFcontaining N2 medium did not differentiate but retained the self-renewal ability, when they are cultured in bFGF-containing N2 medium [17,24]. Consistent with the in vivo results, Sur8 expression levels monitored in this in vitro system were reduced, and levels of Tuj1 and PCNA were increased and decreased, respectively, in NPCs induced to differentiate by the removal of bFGF (Fig.…”

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior

“…FGF-2 is a potent neurogenic factor promoting early neurogenesis, supporting proliferation of neural stem cells and progenitors and enhancing the survival of mature neurons. [69][70][71][72] Moreover, a reduction in FGF-2 expression and an increase in FGF receptor expression in the frontal cortex and hippocampus were observed in post-mortem human brain samples of patients suffering from major depression. 73,74 Similarly, animal models further support the role of the FGF system in depression and its potential involvement in antidepressant treatment.…”

FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

“…VEGF treatment leads to the recruitment of Nck, p21-activated kinase, Crk, Grb2, and protein kinase C to FRS2 [10]. FRS2 serves as an alternative link of FGFRs to PKC activation in the central nervous system [39]. Most importantly, the embryos of FGFR1(Δ)FRS/ΔFRS mice, in which the FRS2-binding site on FGFR1 is deleted, die during late embryogenesis and exhibit defects in neural tube closure.…”