title: Functional SDF1 alpha/CXCR4 signaling in the developing spinal cord.
abstract: Stromal cell-derived factor (SDF1) and its cognate receptor CXCR4 have been shown to play a central role in the development of the cerebellum, hippocampus, and neocortex. However, little is known about the functions of SDF1/CXCR4 in early spinal cord progenitor cell differentiation. Here, we show that a functional SDF1alpha/CXCR4 signaling pathway is present in developing spinal cord cells (a spliced variant of SDF1). RT-PCR analysis of SDF1alpha and CXCR4 showed that they were present in E10.5 neural tube and their expression increased as neuroepithelial cells differentiated into more committed spinal cord progenitors. Stimulation of the more differentiated progenitors (E14.5) with SDF1alpha resulted in rapid activation of the extracellular signal-regulated kinase (ERK)1/2. This SDF1alpha-induced ERK activity was dose dependent and could be inhibited by pre-treatment of the cells with either pertussis toxin, an inactivator of G-protein-coupled receptors, or PD98059, a MEK1 inhibitor. Concomitant with ERK activation, SDF1alpha also activated the downstream transcription factor Ets, a substrate for ERK phosphorylation. Further, downstream activation of genes associated with cell survival, differentiation and migration was assessed using a G-protein-coupled receptor pathway-focused microarray. We found that 23 genes, including PDK1, Egr-1, Grm5, and E-selectin, were up-regulated by SDF1alpha. Furthermore, SDF1alpha induced chemotaxis in both neural and glial progenitors in in vitro migration assays. Pre-treatment of the cells with either pertussis toxin or PD98059 completely inhibited SDF1alpha-induced chemotaxis. Thus, our data suggest that SDF1alpha may function through a CXCR4/ERK/Ets-linked signalling pathway in spinal cord neural development to modulate migration of progenitor cells.
authors.affiliation: Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Luo
authors.forename: Jingli
authors.initials: J
authors.lastname: Cai
authors.forename: Haipeng
authors.initials: H
authors.lastname: Xue
authors.forename: Takumi
authors.initials: T
authors.lastname: Miura
authors.forename: Mahendra S
authors.initials: MS
authors.lastname: Rao
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D005260:Female; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000196:embryology* / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4