title: Redirection of doublecortin-positive cell migration by over-expression of the chemokines MCP-1, MIP-1α and GRO-α in the adult rat brain.
abstract: Inflammation-induced chemoattraction plays a major role in adult subventricular zone (SVZ)-derived precursor cell migration following neural cell loss, in particular through the release of chemokines by activated microglia and macrophages. We previously demonstrated that monocyte chemotactic protein-1 (MCP-1) (chemokine (c-c motif) ligand (CCL)2), macrophage inflammatory protein-1α (MIP-1α) (CCL3) and growth regulatory protein-α (GRO-α) (chemokine (c-x-c motif) ligand (CXCL)1) are up-regulated following neural cell loss in the adult striatum and act as potent chemoattractants for SVZ-derived precursor cells in vitro. Based on these observations, the current study aimed to examine the individual effect of MCP-1, MIP-1α and GRO-α on the migration of adult SVZ-derived neural precursor cells in vivo. To address this without the confounding effects of injury-induced chemotactic cues, adeno-associated viral (AAV)2-mediated in vivo gene transfer was used to ectopically express either MCP-1, MIP-1α or GRO-α, or the control red fluorescent protein (RFP) in the normal adult rat striatum. The extent of doublecortin (Dcx)-positive cell recruitment from the SVZ into the striatal parenchyma was then determined at 4 and 8weeks following AAV2 injection. Ectopic expression either of MCP-1 or MIP-1α in the normal adult rat brain significantly increased the number of Dcx-positive cells and the extent of their migration into the striatum at both 4 and 8weeks after vector injection but did not promote either precursor cell proliferation or neural differentiation. In contrast, while over-expression of GRO-α 4weeks after vector injection induced a significant increase in Dcx-positive cell migration compared to control, this effect was reduced to control levels by 8weeks post injection. Further, direct comparison between MCP-1, MIP-1α and GRO-α at both 4 and 8weeks post vector injection indicated that GRO-α may have a reduced effect in inducing Dcx-positive cell migration when compared to MCP-1. Combined, these results confirm that over-expression of the chemokines MCP-1, MIP-1α and GRO-α can override cues directing precursor cell migration along the rostral migratory stream (RMS) and provides a mechanism by which neural precursor cell migration can be redirected into a non-neurogenic region. Differences in the migratory effect observed between individual chemokine may be due to ligand-binding affinity and/or receptor expression on SVZ-derived precursor cells.
authors.affiliation: Department of Pharmacology & Clinical Pharmacology, Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address: siu.tang@auckland.ac.nz.
authors.forename: S K
authors.initials: SK
authors.lastname: Tang
authors.affiliation: Department of Pharmacology & Clinical Pharmacology, Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address: r.knobloch@auckland.ac.nz.
authors.forename: R A
authors.initials: RA
authors.lastname: Knobloch
authors.affiliation: Department of Pharmacology & Clinical Pharmacology, Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address: c.maucksch@auckland.ac.nz.
authors.forename: C
authors.initials: C
authors.lastname: Maucksch
authors.affiliation: Department of Pharmacology & Clinical Pharmacology, Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address: b.connor@auckland.ac.nz.
authors.forename: B
authors.initials: B
authors.lastname: Connor
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis*; D058953:Neural Stem Cells / Q000737:chemistry / Q000502:physiology; D009479:Neuropeptides / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054360:Chemokine CXCL1; D018925:Chemokines; C513297:Cxcl1 protein, rat; C000714328:DCX protein, human; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides
keywords: 3,3′ diaminobenzidine; 5-chloro-2-deoxyuridine; 5′-iodo-2′-deoxyuridine; AAV; AP; CCL; CCR; CXCL; CXCR; CldU; DAB; DV; Dcx; GFP; GRO-α; HA; IdU; MAP2; MCP-1; MIP-1α; ML; PBS; RMS; RV; SVZ; adeno-associated viral; anterior posterior; chemokine; chemokine (c-c motif) ligand; chemokine (c-c motif) receptor; chemokine (c-x-c motif) ligand; chemokine (c-x-c motif) receptor; dorsal ventral; doublecortin; green fluorescent protein; growth regulatory protein-α; human agglutinin; macrophage inflammatory protein-1α; medial lateral; microtubule associated protein-2; migration; monocyte chemotactic protein-1; phosphate-buffered saline; retroviral vector; rostral migratory stream; subventricular zone