Selective ablation of alphav integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death.
Mouse embryos genetically null for all alphav 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 alphav expression in the vascular endothelium has no detectable effect on cerebral blood vessel development, whereas deletion of alphav expression in central nervous system glial cells leads to embryonic and neonatal cerebral hemorrhage. Conditional deletion of alphav 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 alphav 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 alphav integrins expressed on axons in the postnatal central nervous system.
McCarty
Joseph H
JH
Center for Cancer Research, Massachusetts Institute of Technology, 40 Ames Street, E17-227, Cambridge, MA 02139, USA.
Lacy-Hulbert
Adam
A
Charest
Alain
A
Bronson
Roderick T
RT
Crowley
Denise
D
Housman
David
D
Savill
John
J
Roes
Jürgen
J
Hynes
Richard O
RO
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001369:Axons / Q000378:metabolism*; D001522:Behavior, Animal; D001921:Brain / Q000196:embryology; D002490:Central Nervous System / Q000502:physiology*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000235:genetics / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D013997:Time Factors
D039564:Integrin alphaV; D016023:Integrins