title: 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.
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of Ministry of Education, Neuroscience Center of Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xiao
authors.forename: Chun
authors.initials: C
authors.lastname: Hu
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yang
authors.forename: Dazhi
authors.initials: D
authors.lastname: Guo
authors.forename: Cui
authors.initials: C
authors.lastname: Li
authors.forename: Weiran
authors.initials: W
authors.lastname: Shen
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Liu
authors.forename: Huang
authors.initials: H
authors.lastname: Aijun
authors.forename: Wang
authors.initials: W
authors.lastname: Dan
authors.forename: Cheng
authors.initials: C
authors.lastname: He
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; D016202:N-Methylaspartate; D020830:rac1 GTP-Binding Protein
keywords: ERK; NMDA receptors; Tiam1; migration; oligodendrocyte precursor cells