MASH1/Ascl1a leads to GAP43 expression and axon regeneration in the adult CNS.
MASH1/Ascl1a leads to GAP43 expression and axon regeneration in the adult CNS.
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DOI：
10.1371/journal.pone.0118918
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Bunge MB
中科院分区：
文献类型：
--
作者：
Williams RR;Venkatesh I;Pearse DD;Udvadia AJ;Bunge MB
与成年哺乳动物的CNS神经元不同，鱼类和胚胎哺乳动物的神经元在损伤后可以再生轴突。这些不同的再生反应部分由选择转录因子的生长相关表达介导。碱性螺旋-环-螺旋（bHLH）转录因子MASH 1/Ascl 1a在许多神经元亚型的发育过程中瞬时表达，并调节介导细胞命运决定和分化的基因的表达。在成年斑马鱼（Danio rerio）中，Ascl 1a也在视神经挤压后再生轴突的视网膜神经节细胞（RGC）中瞬时表达。利用具有3.6 kb GAP 43启动子的转基因斑马鱼，其驱动增强型绿色荧光蛋白（EGFP）的表达，我们观察到与对照相比，Ascl 1a表达的敲低降低了损伤后的再生gap 43基因表达和轴突生长。在哺乳动物中，去甲肾上腺素能脑干神经元的发育需要MASH 1表达。然而，与斑马鱼RGCs相反，脊髓损伤（SCI）后，MASH 1在哺乳动物脑干中不表达。因此，我们利用腺相关病毒（AAV）载体在4个月大的大鼠（褐家鼠）脑干神经元中过表达MASH 1，试图促进SCI后轴突再生。我们发现，在完全横断胸脊髓和植入雪旺细胞桥后，与对照组相比，表达MASH 1的动物表现出去甲肾上腺素能轴突再生增加和后肢关节运动改善。总之，这些数据表明，MASH 1/Ascl 1a是脊椎动物轴突生长的基本调节因子，可以诱导神经元内在状态的改变，以促进对CNS损伤的功能性再生。
Unlike CNS neurons in adult mammals, neurons in fish and embryonic mammals can regenerate their axons after injury. These divergent regenerative responses are in part mediated by the growth-associated expression of select transcription factors. The basic helix-loop-helix (bHLH) transcription factor, MASH1/Ascl1a, is transiently expressed during the development of many neuronal subtypes and regulates the expression of genes that mediate cell fate determination and differentiation. In the adult zebrafish (Danio rerio), Ascl1a is also transiently expressed in retinal ganglion cells (RGCs) that regenerate axons after optic nerve crush. Utilizing transgenic zebrafish with a 3.6 kb GAP43 promoter that drives expression of an enhanced green fluorescent protein (EGFP), we observed that knock-down of Ascl1a expression reduces both regenerative gap43 gene expression and axonal growth after injury compared to controls. In mammals, the development of noradrenergic brainstem neurons requires MASH1 expression. In contrast to zebrafish RGCs, however, MASH1 is not expressed in the mammalian brainstem after spinal cord injury (SCI). Therefore, we utilized adeno-associated viral (AAV) vectors to overexpress MASH1 in four month old rat (Rattus norvegicus) brainstem neurons in an attempt to promote axon regeneration after SCI. We discovered that after complete transection of the thoracic spinal cord and implantation of a Schwann cell bridge, animals that express MASH1 exhibit increased noradrenergic axon regeneration and improvement in hindlimb joint movements compared to controls. Together these data demonstrate that MASH1/Ascl1a is a fundamental regulator of axonal growth across vertebrates and can induce modifications to the intrinsic state of neurons to promote functional regeneration in response to CNS injury.
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影响因子：
5.3
作者：
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通讯作者：
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影响因子：
4.2
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REIER, PJ
DOI：
10.1073/pnas.0306988101
发表时间：
2004-04-13
影响因子：
11.1
作者：
Hu, Y;Wang, T;Gordon, JI
通讯作者：
Gordon, JI