NMDA receptor couples Rac1-GEF Tiam1 to direct oligodendrocyte precursor cell migration

Abstract

Oligodendrocyte precursor cells (OPCs) originate from restricted regions of the brain and migrate into the developing white matter, where they differentiate into oligodendrocytes and myelinate axons in the central nervous system (CNS). The molecular mechanisms that orchestrate these long distance trips of OPCs to populate throughout the CNS are poorly understood. Emerging evidence has argued the expression of N-methyl-d-aspartic acid (NMDA) receptors (NMDARs) in oligodendrocyte lineage cells in vivo, but their physiological function remains elusive. We have previously demonstrated the expression and function of NMDARs in OPC differentiation and myelination/remyelination. Here, we show that NMDARs stimulation promotes OPC migration both by chemotaxis and chemokinesis as demonstrated by various cell migration systems including Boyden transwell, single cell, matrix-gel cell mass, and SVZ tissue explants assays. The pro-migration effect of NMDAR can be abolished by either pharmacological inhibition or shRNA knock down of the T lymphoma invasion and metastasis 1 (Tiam1), a Rac1 guanine nucleotide exchange factor (Rac1-GEF) which is coexpressed and interacts with NMDAR in OPCs. Moreover, NMDAR stimulation evokes cascade activation of the Tiam1/Rac1/ERK signaling pathway which mediates its effect on OPC migration. We also show that glutamate released from cultured cortical neuron promotes OPCs migration via NMDAR, and that antagonism of NMDAR or inhibition of Tiam1 blocks the endogenous glutamate-induced OPCs migration from SVZ to cortical plate in the embryonic brain slice culture. Thus, our result suggests a critical role of NMDAR in regulation of OPCs migration during CNS development by coupling to and activating the Tiam1/Rac1 pathway.

Trans-regulation of oligodendrocyte myelination by neurons through small GTPase Arf6-regulated secretion of fibroblast growth factor-2

“…The results showed that the numbers of Olig2/BrdUdouble-positive cells are unchanged in the SVZ but are reduced in the Fim and CC in the N-Arf6-CKO mice. These results led to the conclusion that neuronal Arf6 plays an important role in OPC migration from the SVZ to the Fim and CC but not in NSC proliferation/differentiation, consistent with reports that OPCs differentiated from NSCs in the SVZ migrate to target areas in the postnatal brain [19][20][21][22][23] . However, it is still possible that proliferative NSCs in brain regions other than the SVZ differentiate into OPCs that migrate to the Fim and CC.…”

Glutamate signalling: A multifaceted modulator of oligodendrocyte lineage cells in health and disease

“…Characteristically, OPCs are motile cells which can migrate long distances and continuously survey their environment via extended filopodia (Hughes et al, 2013). The activation of both AMPA/kainate and NMDA receptors in OPCs has been shown to increase motility through the modulation of the adhesion molecule PSA-NCAM or the modification of Tiam1 signalling, which induces lamellipodium growth of leading OPC processes (Xiao et al, 2013). AMPA/kainate receptor activation also leads to the composition of an α v -integrin and proteolipid protein (PLP) complex which associates with the AMPA receptor subunit GluA2 -a subunit which makes AMPA receptors impermeable to calcium (Gudz et al, 2006; see Figure 2).…”

Intertwining extracellular nucleotides and their receptors with Ca2+in determining adult neural stem cell survival, proliferation and final fate

“…Several studies have later addressed the importance of Ca 2þ signalling in process extension and OPC migration [58][59][60][61][62], in their differentiation, myelination and re-myelination capacity [63 -66], and in retraction of membrane sheaths and cell death in mature mouse oligodendrocytes [67].…”