Crosstalk between Notch and Sonic hedgehog signaling in a mouse model of amyotrophic lateral sclerosis.
Crosstalk between Notch and Sonic hedgehog signaling in a mouse model of amyotrophic lateral sclerosis.
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DOI：
10.1097/wnr.0000000000000725
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发表时间：
2017-02-08
期刊：
影响因子：
1.7
通讯作者：
Turnbull J
中科院分区：
文献类型：
--
作者：
Ma X;Drannik A;Jiang F;Peterson R;Turnbull J
发育形态原Sonic hedgehog （Shh）可能在成人运动神经元中继续发挥持续作用，可能与肌萎缩侧索硬化症等运动神经元疾病相关。Shh信号通路尚不完全清楚，可能与其他信号通路相互作用。我们将重点放在Notch上，并首先表明在Notch抑制剂DAPT浓度增加的情况下，Shh light II细胞中Gli报告基因的光输出几乎呈线性减少（r2=0.982）。其次，在超氧化物歧化酶突变小鼠而非对照小鼠的脊髓中，Notch信号的一个关键标记物随着年龄的增长而变化。在出现临床症状之前，Notch细胞内结构域主要在运动神经元中表达，但在125日龄时，Notch细胞内结构域在运动神经元中的表达明显减少，而在邻近的星形胶质细胞中表达增加。第三，突变型超氧化物歧化酶小鼠脊髓运动神经元中Gli蛋白表达平行减少，与观察到的Notch信号减少和Gli远离细胞核的重新分布一致。因此，运动神经元Notch信号的减少和Shh信号的相关变化与疾病表达同时发生，这可能导致肌萎缩性侧索硬化症运动神经元的功能障碍和死亡。
The developmental morphogen Sonic hedgehog (Shh) may continue to play a sustaining role in adult motor neurons, of potential relevance to motor neuron diseases including amyotrophic lateral sclerosis. The Shh signaling pathway is incompletely understood and interactions with other signaling pathways are possible. We focus here on Notch, and first show that there is an almost linear reduction in light output from a Gli reporter in Shh Light II cells in the presence of increasing concentrations of the Notch inhibitor DAPT (r2=0.982). Second, in the spinal cord of mutant superoxide dismutase mice, but not control mice, a key marker of Notch signaling changes with age. Before the onset of clinical signs, the Notch intracellular domain is expressed predominantly in motor neurons, but by 125 days of age, Notch intracellular domain expression is markedly reduced in motor neurons and increased in neighboring astroglia. Third, there is a parallel reduction in Gli protein expression in mutant superoxide dismutase mouse spinal motor neurons, consistent with the observed reduction in Notch signaling and also a redistribution of Gli away from the nucleus. Thus, there is a reduction in motor neuronal Notch signaling and associated changes in Shh signaling, occurring coincidentally with disease expression, that may contribute toward the dysfunction and death of motor neurons in amyotrophic lateral sclerosis.