Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury.
Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury.
复制标题
CSPG受体LAR磷酸酶在CNS损伤后限制轴突再生中的作用。
DOI：
10.1016/j.nbd.2014.08.030
复制
发表时间：
2015-01
影响因子：
6.1
通讯作者：
Li, Shuxin
中科院分区：
文献类型：
--
作者：
Xu, Bin;Park, Dongsun;Ohtake, Yosuke;Li, Hui;Hayat, Umar;Liu, Junjun;Selzer, Michael E.;Longo, Frank M.;Li, Shuxin
关键词：
细胞外基质分子硫酸软骨素蛋白聚糖（CSPG）在瘢痕组织中高度上调，并形成CNS轴突再生的有效化学屏障。最近的研究表明受体蛋白酪氨酸磷酸酶σ（PTPσ）及其亚家族成员白细胞共同抗原相关磷酸酶（LAR）作为跨膜受体介导CSPG抑制作用。PTPσ缺乏可增加脊髓损伤后上行轴突向瘢痕组织的再生长和下行皮质脊髓束（CST）轴突向脊髓尾侧的再生长。药理学LAR抑制增强SCI小鼠中的轴突生长。然而，转基因LAR缺失对轴突生长的影响以及LAR在调节其他纤维束再生中的作用还没有研究。在这里，我们研究了LAR在限制缺陷小鼠受损的下行CNS轴突再生中的作用。LAR缺失增加了背侧过度半横断后轴突向瘢痕组织和尾侧脊髓的再生长。LAR缺失也刺激CST纤维再生长到脊髓尾侧。LAR蛋白在损伤后数天至数周上调，并共同定位于肾上腺素能和CST轴突。此外，LAR缺失通过增加BMS运动评分和步长以及减少网格行走错误来改善功能恢复。这是第一个证明LAR在限制受损CNS轴突再生中的关键作用的转基因研究。
Extracellular matrix molecule chondroitin sulfate proteoglycans (CSPGs) are highly upregulated in scar tissues and form a potent chemical barrier for CNS axon regeneration. Recent studies support that the receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member leukocyte common antigen related phosphatase (LAR) act as transmembrane receptors to mediate CSPG inhibition. PTPσ deficiency increased regrowth of ascending axons into scar tissues and descending corticospinal tract (CST) axons into the caudal spinal cord after spinal cord injury (SCI). Pharmacological LAR inhibition enhanced serotonergic axon growth in SCI mice. However, transgenic LAR deletion on axon growth in vivo and role of LAR in regulating regrowth of other fiber tracts have not been studied. Here, we studied role of LAR in restricting regrowth of injured descending CNS axons in deficient mice. LAR deletion increased regrowth of serotonergic axons into scar tissues and caudal spinal cord after dorsal overhemitransection. LAR deletion also stimulated regrowth of CST fibers into the caudal spinal cord. LAR protein was upregulated days to weeks after injury and co-localized to serotonergic and CST axons. Moreover, LAR deletion improved functional recovery by increasing BMS locomotor scores and stride length and reducing grid walk errors. This is the first transgenic study that demonstrates crucial role of LAR in restricting regrowth of injured CNS axons.
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