Combined chondroitinase and KLF7 expression reduce net retraction of sensory and CST axons from sites of spinal injury.
Combined chondroitinase and KLF7 expression reduce net retraction of sensory and CST axons from sites of spinal injury.
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DOI：
10.1016/j.nbd.2016.12.010
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发表时间：
2017-03
影响因子：
6.1
通讯作者：
Blackmore MG
中科院分区：
文献类型：
--
作者：
Wang Z;Winsor K;Nienhaus C;Hess E;Blackmore MG
中枢神经系统中的轴突再生受到抑制性细胞外信号和某些CNS群体中轴突生长的固有低能力的限制。硫酸软骨素蛋白聚糖（CSPG）是CNS中轴突生长的充分研究的抑制剂，并且已显示通过软骨素酶降解CSPG可改善受损轴突的延伸。或者，轴突生长可以通过靶向神经元的内在生长能力，通过强制表达再生相关的转录因子来改善。例如，Krüppel样因子7（KLF 7）和VP 16结构域的转录活性嵌合体在皮质脊髓束神经元中表达时改善轴突生长。在这里，我们测试了软骨素酶和VP 16-KLF 7的联合表达将导致脊髓损伤后轴突生长的进一步改善的假设。软骨素酶通过脊髓中细胞的病毒转导表达，而VP 16-KLF 7在背根神经节或皮质脊髓束（CST）神经元的感觉神经元中病毒表达。切断背柱后，软骨素酶和VP 16-KLF 7都增加了切断的感觉轴突与损伤部位的接近度。同样，在完全挤压损伤后，VP 16-KLF 7表达增加了CST轴突向损伤部位的接近。然而，在这两个范例中，用软骨素酶或VP 16-KLF 7进行的单一或组合治疗都不能使损伤远端再生生长。这些结果证实了CSPG抑制和低KLF 7活性在确定轴突从脊髓损伤部位的净回缩中的作用，同时表明其他因素起作用以限制完全再生反应。
Axon regeneration in the central nervous system is limited both by inhibitory extracellular cues and by an intrinsically low capacity for axon growth in some CNS populations. Chondroitin sulfate proteoglycans (CSPGs) are well-studied inhibitors of axon growth in the CNS, and degradation of CSPGs by chondroitinase has been shown to improve the extension of injured axons. Alternatively, axon growth can be improved by targeting the neuron-intrinsic growth capacity through forced expression of regeneration-associated transcription factors. For example, a transcriptionally active chimera of Krüppel-like Factor 7 (KLF7) and a VP16 domain improves axon growth when expressed in corticospinal tract neurons. Here we tested the hypothesis that combined expression of chondroitinase and VP16-KLF7 would lead to further improvements in axon growth after spinal injury. Chondroitinase was expressed by viral transduction of cells in the spinal cord, while VP16-KLF7 was virally expressed in sensory neurons of the dorsal root ganglia or corticospinal tract (CST) neurons. After transection of the dorsal columns, both chondroitinase and VP16-KLF7 increased the proximity of severed sensory axons to the injury site. Similarly, after complete crush injuries, VP16-KLF7 expression increased the approach of CST axons to the injury site. In neither paradigm however, did single or combined treatment with chondroitinase or VP16-KLF7 enable regenerative growth distal to the injury. These results substantiate a role for CSPG inhibition and low KLF7 activity in determining the net retraction of axons from sites of spinal injury, while suggesting that additional factors act to limit a full regenerative response.
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影响因子：
3.5
作者：
Blackmore, Murray G.;Moore, Darcie L.;Smith, Robin P.;Goldberg, Jeffrey L.;Bixby, John L.;Lemmon, Vance P.
通讯作者：
Lemmon, Vance P.
影响因子：
5.3
作者：
Jones, LL;Margolis, RU;Tuszynski, MH
通讯作者：
Tuszynski, MH
影响因子：
5.3
作者：
Broude, E;McAtee, M;Bregman, BS
通讯作者：
Bregman, BS
影响因子：
4.2
作者：
Iseda, Tsutomu;Okuda, Tetsuhito;Grumet, Martin
通讯作者：
Grumet, Martin
影响因子：
3.7
作者：
Alluin O;Delivet-Mongrain H;Gauthier MK;Fehlings MG;Rossignol S;Karimi-Abdolrezaee S
通讯作者：
Karimi-Abdolrezaee S