title: Physiological electrical signals promote chain migration of neuroblasts by up-regulating P2Y1 purinergic receptors and enhancing cell adhesion.
abstract: Neuroblasts migrate as directed chains of cells during development and following brain damage. A fuller understanding of the mechanisms driving this will help define its developmental significance and in the refinement of strategies for brain repair using transplanted stem cells. Recently, we reported that in adult mouse there are ionic gradients within the extracellular spaces that create an electrical field (EF) within the rostral migratory stream (RMS), and that this acts as a guidance cue for neuroblast migration. Here, we demonstrate an endogenous EF in brain slices and show that mimicking this by applying an EF of physiological strength, switches on chain migration in mouse neurospheres and in the SH-SY5Y neuroblastoma cell line. Firstly, we detected a substantial endogenous EF of 31.8 ± 4.5 mV/mm using microelectrode recordings from explants of the subventricular zone (SVZ). Pharmacological inhibition of this EF, effectively blocked chain migration in 3D cultures of SVZ explants. To mimic this EF, we applied a physiological EF and found that this increased the expression of N-cadherin and β-catenin, both of which promote cell-cell adhesion. Intriguingly, we found that the EF up-regulated P2Y purinoceptor 1 (P2Y1) to contribute to chain migration of neuroblasts through regulating the expression of N-cadherin, β-catenin and the activation of PKC. Our results indicate that the naturally occurring EF in brain serves as a novel stimulant and directional guidance cue for neuronal chain migration, via up-regulation of P2Y1.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK, l.cao@abdn.ac.uk.
authors.forename: Lin
authors.initials: L
authors.lastname: Cao
authors.forename: Jin
authors.initials: J
authors.lastname: Pu
authors.forename: Roderick H
authors.initials: RH
authors.lastname: Scott
authors.forename: Jared
authors.initials: J
authors.lastname: Ching
authors.forename: Colin D
authors.initials: CD
authors.lastname: McCaig
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena; D005260:Female; D006801:Humans; D020547:Lateral Ventricles / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D046509:Tissue Culture Techniques; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D058472:Receptors, Purinergic P2Y1; D051176:beta Catenin; D000255:Adenosine Triphosphate; D011493:Protein Kinase C
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