Non-viral-mediated suppression of AMIGO3 promotes disinhibited NT3-mediated regeneration of spinal cord dorsal column axons.
Non-viral-mediated suppression of AMIGO3 promotes disinhibited NT3-mediated regeneration of spinal cord dorsal column axons.
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DOI：
10.1038/s41598-018-29124-z
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发表时间：
2018-07-16
影响因子：
4.6
通讯作者：
Ahmed Z
中科院分区：
文献类型：
--
作者：
Almutiri S;Berry M;Logan A;Ahmed Z
在对成熟的中枢神经系统（CNS）损伤后，髓磷脂衍生的抑制性配体与轴突生长锥上表达的Nogo-66三联受体复合物结合，并通过RhoA途径诱导生长锥塌陷，所述Nogo-66三联受体复合物由LINGO-1和p75 NTR/TROY组成。我们还表明，拟南芥素诱导的基因和开放阅读框架-3（AMIGO 3）取代LINGO-1，并可以信号轴突生长锥崩溃。在这里，我们研究了背根神经节神经元（DRGN）轴突/神经突治疗后的短发夹RNA（sh）AMIGO 3质粒与非病毒在体内jetPEI载体，并在体外和体内的促生存/轴突神经营养因子（NT）3。含有shAMIGO 3和NT 3的双顺反子质粒在培养的DRGN中敲低>75%的AMIGO 3 mRNA并显著过表达NT 3产生。在体内，DRG内注射含有shAMIGO 3/gfp和shAMIGO 3/nt 3的体内jetPEI质粒均敲低DRGN中的AMIGO 3表达，并与NT 3过表达相结合，促进DC轴突再生，恢复损伤部位的复合动作电位传导，改善感觉和运动功能。这些发现表明，体内-jetPEI是一种潜在的非病毒的、可翻译的DRGN体内递送载体，并且AMIGO 3的抑制解除了轴突切断的DRGN的生长，使得NT 3能够刺激其DC轴突的再生并增强功能恢复。
After injury to the mature central nervous system (CNS), myelin-derived inhibitory ligands bind to the Nogo-66 tripartite receptor complex expressed on axonal growth cones, comprised of LINGO-1 and p75NTR/TROY and induce growth cone collapse through the RhoA pathway. We have also shown that amphoterin-induced gene and open reading frame-3 (AMIGO3) substitutes for LINGO-1 and can signal axon growth cone collapse. Here, we investigated the regeneration of dorsal root ganglion neuron (DRGN) axons/neurites after treatment with a short hairpin RNA (sh) AMIGO3 plasmid delivered with a non-viral in vivo-jetPEI vector, and the pro-survival/axogenic neurotrophin (NT) 3 in vitro and in vivo. A bicistronic plasmid, containing both shAMIGO3 and NT3 knocked down >75% of AMIGO3 mRNA in cultured DRGN and significantly overexpressed NT3 production. In vivo, intra-DRG injection of in vivo-jetPEI plasmids containing shAMIGO3/gfp and shAMIGO3/nt3 both knocked down AMIGO3 expression in DRGN and, in combination with NT3 overexpression, promoted DC axon regeneration, recovery of conduction of compound action potentials across the lesion site and improvements in sensory and locomotor function. These findings demonstrate that in vivo-jetPEI is a potential non-viral, translatable DRGN delivery vehicle in vivo and that suppression of AMIGO3 disinhibits the growth of axotomised DRGN enabling NT3 to stimulate the regeneration of their DC axons and enhances functional recovery.
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影响因子：
3.7
作者：
Bonnet, Marie-Elise;Erbacher, Patrick;Bolcato-Bellemin, Anne-Laure
通讯作者：
Bolcato-Bellemin, Anne-Laure
影响因子：
2.7
作者：
Kanagal, Srikanth G.;Muir, Gillian D.
通讯作者：
Muir, Gillian D.
影响因子：
5.3
作者：
Hains, BC;Saab, CY;Waxman, SG
通讯作者：
Waxman, SG
影响因子：
3.5
作者：
Ahmed, Z;Dent, RG;Logan, A
通讯作者：
Logan, A
RGMA抑制可促进脊髓损伤后的轴突生长和恢复。
DOI：
10.1083/jcb.200508143
发表时间：
2006-04-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hata K;Fujitani M;Yasuda Y;Doya H;Saito T;Yamagishi S;Mueller BK;Yamashita T
通讯作者：
Yamashita T