Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration

Abstract

Fibroblast growth factor-2 (FGF2), also known as basic FGF, is a multi-functional growth factor. One of the 22-member FGF family, it signals through receptor tyrosine kinases encoding FGFR1-4. FGF2 activates FGFRs in cooperation with heparin or heparin sulfate proteoglycan to induce its pleiotropic effects in different tissues and organs, which include potent angiogenic effects and important roles in the differentiation and function of the central nervous system (CNS). FGF2 is crucial to development of the CNS, which explains its importance in adult neurogenesis. During development, high levels of FGF2 are detected from neurulation onwards. Moreover, developmental expression of FGF2 and its receptors is temporally and spatially regulated, concurring with development of specific brain regions including the hippocampus and substantia nigra pars compacta. In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation. Because of its importance in adult neurogenesis and neuroinflammation, manipulation of FGF2/FGFR1 signaling has been a focus of therapeutic development for neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and traumatic brain injury. Novel strategies include intranasal administration of FGF2, administration of an NCAM-derived FGFR1 agonist, and chitosan-based nanoparticles for the delivery of FGF2 in pre-clinical animal models. In this review, we highlight current research towards therapeutic interventions targeting FGF2/FGFR1 in neurodegenerative disorders.

Figure 1. Potential mechanism of FGF2-induced neurogenesis

A) Above: Heat map of differentially expressed genes derived from Affymetrix Genechip analysis of APP+PS1 mice infected with AAV2/1-FGF2 or AAV2/1-GFP vs. wildtype (WT) uninfected control. Several neurogenesis-related functions, such as neuronal differentiation, apoptosis, synaptic plasticity and nervous system development are among the most highly differentially regulated gene clusters. Below: 5 most significantly differentially regulated genes, as measured by one-way ANOVA and Tukey post hoc. PKP2, plakophilin 2; CPNE7, copine VII; PROX1, prospero-related homeobox 1; RAS1, RAS, dexamethasone-induced 1; SEMA5A, semaphorin-5A. B) Scheme of potential mechanism of FGF2-induced neurogenesis: binding of high-molecular weight (HMW) FGF2 to nuclear FGFR1 leads to induction of neurogenic genes, such as PROX1 and SEMA5A, which are highly expressed in hippocampus of AAV2/1-FGF2 infected vs. AAV2/1-GFP infected APP+PS1 mice (see A). HMW FGF2 also binds to anti-apoptotic molecules apoptosis inhibitor 5 (Api5) and survival motor neuron 1 (SMN) to potentiate cell survival.

Figure 2. Scheme of neuroimmunomodulation of CD200 signaling by FGF2 signaling

Activation of FGFR leads to enhanced CD200 expression, which leads to subsequent activation of anti-inflammatory pathways via microglial CD200 receptor (CD200R) activation. This pathway may be disturbed in AD patients due to CD200 decrease by amyloid-β (Aβ), pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs) recognized by microglia, leading to neuroinflammation-induced suppression of LTP, synaptic transmission and neuronal viability in AD brain.