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First published online 2 December 2004
doi: 10.1242/dev.01551

Development 132, 165-176 (2005)
Published by The Company of Biologists 2005
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Selective ablation of {alpha}v integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death

Joseph H. McCarty1,*, Adam Lacy-Hulbert1,2,3, Alain Charest1, Roderick T. Bronson3, Denise Crowley1,*, David Housman1, John Savill2, Jürgen Roes4 and Richard O. Hynes1,*,{dagger}

1 Center for Cancer Research, Massachusetts Institute of Technology, 40 Ames Street, E17-227, Cambridge, MA 02139, USA
2 Medical Research Council and University of Edinburgh Center for Inflammation Research, Teviot Place, Edinburgh EH8 9AG, UK
3 Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA
4 Windeyer Institute for Medical Sciences, University College London, 46 Cleveland Street, London W1T 4JF, UK

{dagger} Author for correspondence (e-mail: rohynes{at}mit.edu)

Accepted 28 October 2004

Mouse embryos genetically null for all {alpha}v integrins develop intracerebral hemorrhage owing to defective interactions between blood vessels and brain parenchymal cells. Here, we have used conditional knockout technology to address whether the cerebral hemorrhage is due to primary defects in vascular or neural cell types. We show that ablating {alpha}v expression in the vascular endothelium has no detectable effect on cerebral blood vessel development, whereas deletion of {alpha}v expression in central nervous system glial cells leads to embryonic and neonatal cerebral hemorrhage. Conditional deletion of {alpha}v integrin in both central nervous system glia and neurons also leads to cerebral hemorrhage, but additionally to severe neurological defects. Approximately 30% of these mutants develop seizures and die by 4 weeks of age. The remaining mutants survive for several months, but develop axonal deterioration in the spinal cord and cerebellum, leading to ataxia and loss of hindlimb coordination. Collectively, these data provide evidence that {alpha}v integrins on embryonic central nervous system neural cells, particularly glia, are necessary for proper cerebral blood vessel development, and also reveal a novel function for {alpha}v integrins expressed on axons in the postnatal central nervous system.

Key words: Cerebral hemorrhage, Spastic paraparesis, Ataxia, Mouse


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