ERK1/2 signaling is essential for the chemoattraction exerted by human FGF2 and human anosmin‐1 on newborn rat and mouse OPCs via FGFR1

Abstract

Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration, as well as differentiation events such as myelination. Anosmin-1 is an extracellular matrix (ECM) glycoprotein that interacts with the fibroblast growth factor receptor 1 (FGFR1) to exert its biological actions through this receptor, although the intracellular pathways underlying anosmin-1 signaling remain largely unknown. This protein is defective in the X-linked form of Kallmann syndrome (KS) and has a prominent role in the migration of neuronal and oligodendroglial precursors. We have shown that anosmin-1 exerts a chemotactic effect via FGFR1 on neuronal precursors from the subventricular zone (SVZ) and the essential role of the ERK1/2 signaling. We report here the positive chemotactic effect of FGF2 and anosmin-1 on rat and mouse postnatal OPCs via FGFR1. The same effect was observed with the truncated N-terminal region of anosmin-1 (A1Nt). The introduction in anosmin-1 of the missense mutation F517L found in patients suffering from KS annulled the chemotactic activity; however, the mutant form carrying the disease-causing mutation E514K also found in KS patients, behaved as the wild-type protein. The chemoattraction exhibited by FGF2 and anosmin-1 on OPCs was blocked by the mitogen-activated protein kinase (MAPK) inhibitor U0126, suggesting that the activation of the ERK1/2 MAPK signaling pathway following interaction with the FGFR1 is necessary for FGF2 and anosmin-1 to exert their chemotactic effect. In fact, both proteins were able to induce the phosphorylation of the ERK1/2 kinases after the activation of the FGFR1 receptor.

Age-linked heterogeneity among oligodendrocyte precursor cells in the cerebral cortex of mice and human

“…We first confirmed that these three cell types expressed FGFR1, the receptor thought to mediate the effects of FGF2 and anosmin-1 on OPC migration (Fig. 4a-f; [27,32,51-53]). It was not surprising to find that the tumor-derived OPCs were more motile in control conditions than non-tumoral OPCs (Table 3).…”

“…FGF-2 and anosmin-1 exert distinct chemotropic effects on rat SVZ neuroblasts, and on rodent embryonic and postnatal OPCs, mainly acting via FGFR1 [19,27,32,33,40,50]. Hence, these molecules represent a good tool to systematically study the physiological heterogeneity in OPC populations, avoiding the variability in structure and origin by restricting our study to cerebral cortex OPCs.…”

“…Proteins from the extracellular matrix (ECM) of CHO cells (CT) and CHO cells stably transfected with an expression plasmid carrying a C-terminal hemaglutinin-tagged (HA) version of the human KAL1 cDNA (A1 [39]) were extracted as described previously [32]. Briefly, the cells were washed once with calcium/magnesium-free Hank’s Balanced Salt Solution (Gibco) and they were then incubated at 4°C for 30 minutes in a gently rocking 10 cm diameter culture dish in 1 ml of 20 mM phosphate buffer (PB, pH 7.4), containing 350 mM NaCl and complete EDTA free protease inhibitor (Roche).…”

Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury

“…In addition, different types of local cues, for example, growth factors, extracellular matrix proteins, axon guidance molecules and neuronal activity can affect OPC migration as well (de Castro & Bribian, 2005;de Castro, Bribian, & Ortega, 2013). Examples of growth factors that promote OPC migration include platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and hepatocyte growth factor (HGF) (Bribian, Barallobre, Soussi-Yanicostas, & de Castro, 2006;Hayakawa et al, 2011Hayakawa et al, , 2012Milner et al, 1997;Murcia-Belmonte, Medina-Rodriguez, Bribian, de Castro, & Esteban, 2014;Yan & Rivkees, 2002). Furthermore, extracellular matrix components such as laminin, fibronectin, vitronectin, anosmin-1, and tenascin-C have been shown to stimulate migration of OPCs (Bribian et al, 2008;Garcion, Faissner, & ffrench-Constant, 2001;Milner, Edwards, Streuli, & Ffrench-Constant, 1996;Murcia-Belmonte et al, 2016).…”

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

“…In addition to the above described direct effects on OLGs, FGF-2 signaling can, at least in vitro , maintain high expression levels for PDGFRα and thereby allow cross-talk between FGF and PDGF signaling to enhance proliferation in the presence of both growth factors (Baron et al, 2000; Bögler et al, 1990; McKinnon et al, 1990; Wolswijk and Noble, 1992). Furthermore, FGF-2 has been implicated to function as a motogenic factor for OPCs and to mediate OPC migration via the activation of FGFR1 and its counteracting ECM glycoprotein anosmin-1 (Bribián et al, 2006; Milner et al, 1997; Murcia-Belmonte et al, 2014; Osterhout et al, 1997). Effects described for FGF-2 on terminally differentiated OLGs include a downregulation of myelin gene expression, re-entry into the cell cycle and a loss of membrane sheath formation mediated by FGFR1, as well as a stimulation of process elongation via FGFR3 (Bansal and Pfeiffer, 1997; Fortin et al, 2005; Fressinaud et al, 1995, 1993; Grinspan et al, 1993, 1996; Hoffman and Duncan, 1995; Muir and Compston, 1996; Wang et al, 2007; Zhou et al, 2006).…”