Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells.
Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells.
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利用人类诱导多能干细胞高产产生运动神经元来模拟脊髓性肌萎缩症的差异表型
DOI：
10.18632/oncotarget.14925
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发表时间：
2017-06-27
期刊：
影响因子：
--
通讯作者：
Chen WJ
中科院分区：
文献类型：
--
作者：
Lin X;Li JJ;Qian WJ;Zhang QJ;Wang ZF;Lu YQ;Dong EL;He J;Wang N;Ma LX;Chen WJ
脊髓性肌萎缩症（SMA）是一种严重的运动神经元疾病，由存活运动神经元1（SMN1）基因突变所致。SMN2是SMN1的旁系同源基因，能够部分代偿SMN1的缺失。根据发病年龄、最高运动功能以及SMN2拷贝数，儿童期发病的SMA可分为三种类型（SMA I - III型）。研究观察到SMN2拷贝数与SMA不同表型之间呈负相关。有趣的是，这种相关性并非绝对。通过利用SMA诱导多能干细胞（iPSCs），我们发现，在SMA III型和SMA I型iPSCs来源的有丝分裂后运动神经元（pMNs）及γ-氨基丁酸（GABA）神经元中，SMN均显著减少。此外，仅在pMNs培养物中观察到SMA III型（SMN2有3个拷贝）与SMA I型（SMN2有2个拷贝）之间SMN表达水平存在显著差异，而在GABA神经元或iPSCs中则无此差异。基于这些发现，我们进一步发现，SMA III型和SMA I型来源的运动神经元（MNs）的轴突生长均受到抑制。同时，在长期培养中也发现SMA III型与SMA I型组之间轴突生长存在显著差异。然而，显著的高兴奋性仅在SMA I型来源的成熟MNs中出现，SMA III型组则无此现象。综上所述，我们认为SMN蛋白是表型修饰的主要因素。我们的数据可能为认识SMA疾病的不同表型提供新的视角。
Spinal muscular atrophy (SMA) is a devastating motor neuron disease caused by mutations of the survival motor neuron 1 (SMN1) gene. SMN2, a paralogous gene to SMN1, can partially compensate for the loss of SMN1. On the basis of age at onset, highest motor function and SMN2 copy numbers, childhood-onset SMA can be divided into three types (SMA I-III). An inverse correlation was observed between SMN2 copies and the differential phenotypes of SMA. Interestingly, this correlation is not always absolute. Using SMA induced pluripotent stem cells (iPSCs), we found that the SMN was significantly decreased in both SMA III and SMA I iPSCs derived postmitotic motor neurons (pMNs) and γ-aminobutyric acid (GABA) neurons. Moreover, the significant differences of SMN expression level between SMA III (3 copies of SMN2) and SMA I (2 copies of SMN2) were observed only in pMNs culture, but not in GABA neurons or iPSCs. From these findings, we further discovered that the neurite outgrowth was suppressed in both SMA III and SMA I derived MNs. Meanwhile, the significant difference of neurite outgrowth between SMA III and SMA I group was also found in long-term cultures. However, significant hyperexcitability was showed only in SMA I derived mature MNs, but not in SMA III group. Above all, we propose that SMN protein is a major factor of phenotypic modifier. Our data may provide a new insight into recognition for differential phenotypes of SMA disease.
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影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
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作者：
Ahmad S;Bhatia K;Kannan A;Gangwani L
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Gangwani L
影响因子：
46.9
作者：
Maury, Yves;Come, Julien;Nedelec, Stephane
通讯作者：
Nedelec, Stephane
影响因子：
30.8
作者：
Lefebvre, S;Burlet, P;Melki, J
通讯作者：
Melki, J
影响因子：
16.6
作者：
Lee, Jong-Hee;Lee, Jung Bok;Bhatia, Mickie
通讯作者：
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