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First published online 22 November 2005
doi: 10.1242/jcs.02680
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Research Article |
1 Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, 505 Parnassus Avenue, San Francisco, CA 94143-0521, USA
2 Department of Neurological Surgery, University of California, 1001 Potrero Avenue, San Francisco, CA 94110, USA
3 Academic Neurosurgery Unit, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK
Author for correspondence (e-mail: verkman{at}itsa.ucsf.edu)
Accepted 8 September 2005
Aquaporin-4, the major water-selective channel in astroglia throughout the central nervous system, facilitates water movement into and out of the brain. Here, we identify a novel role for aquaporin-4 in astroglial cell migration, as occurs during glial scar formation. Astroglia cultured from the neocortex of aquaporin-4-null mice had similar morphology, proliferation and adhesion, but markedly impaired migration determined by Transwell migration efficiency (18±2 vs 58±4% of cells migrated towards 10% serum in 8 hours; P<0.001) and wound healing rate (4.6 vs 7.0 µm/hour speed of wound edge; P<0.001) compared with wild-type mice. Transwell migration was similarly impaired (25±4% migrated cells) in wild-type astroglia after 
90% reduction in aquaporin-4 protein expression by RNA inhibition. Aquaporin-4 was polarized to the leading edge of the plasma membrane in migrating wild-type astroglia, where rapid shape changes were seen by video microscopy. Astroglial cell migration was enhanced by a small extracellular osmotic gradient, suggesting that aquaporin-4 facilitates water influx across the leading edge of a migrating cell. In an in vivo model of reactive gliosis and astroglial cell migration produced by cortical stab injury, glial scar formation was remarkably impaired in aquaporin-4-null mice, with reduced migration of reactive astroglia towards the site of injury. Our findings provide evidence for the involvement of aquaporin-4 in astroglial cell migration, which occurs during glial scar formation in brain injury, stroke, tumor and focal abscess.
Key words: AQP4, Astrocyte, Chemotaxis, Reactive gliosis, Water channel
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