Selective ablation of αv integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death
Selective ablation of αv integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death
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DOI：
10.1242/dev.01551
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发表时间：
2005-01-01
期刊：
影响因子：
4.6
通讯作者：
Hynes, RO
中科院分区：
文献类型：
--
作者：
McCarty, JH;Lacy-Hulbert, A;Hynes, RO
由于血管与脑实质细胞之间的缺陷相互作用，所有alphav整联蛋白的遗传胚胎遗传无效。在这里，我们使用条件敲除技术来解决脑出血是否是由于血管或神经细胞类型的主要缺陷所致。我们表明，在血管内皮中消融AV表达对脑血管发育没有可检测的影响，而中枢神经系统神经胶质细胞中alphav表达的删除会导致胚胎和新生儿脑出血。中枢神经系统神经胶质和神经元中Alphav整联蛋白的条件缺失也导致脑出血，但除了严重的神经系统缺陷外。这些突变体中约有30％发生癫痫发作，并在4周龄时死亡。其余的突变体存活了几个月，但在脊髓和小脑中会出现轴突恶化。导致共济失调和后肢协调的丧失。这些数据共同提供了证据，表明胚胎中枢神经系统神经细胞（尤其是神经胶质）上的Alphav整联蛋白对于适当的脑血管发育是必需的。并揭示了在产后中枢神经系统中轴突上表达的alphav整联蛋白的新功能。
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 av 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.