Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy.
Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy.
复制标题
DOI：
10.3390/ijms22105237
复制
发表时间：
2021-05-15
影响因子：
5.6
通讯作者：
Sorokin A
中科院分区：
文献类型：
--
作者：
Miller B;Kostrominova TY;Geurts AM;Sorokin A
普遍表达的接头蛋白Shc以p46Shc、p52Shc和p66Shc三种亚型存在，它们在细胞中执行明显不同的作用。目前对p46Shc的作用研究还不够深入，本研究的目的是进一步探讨其功能意义。我们开发了缺乏p52Shc和p46Shc亚型的独特的大鼠突变体(p52Shc/46Shc-KO)，并对步态受损的亲本和转基因大鼠的骨骼肌和心肌进行了组织学分析。P52Shc/46Shc-KO大鼠表现出与步态受损相关的严重功能异常。我们对p52Shc/46Shc-KO大鼠坐骨神经横切面的轴突和髓鞘进行了分析，发现存在显著的异常。根据p52Shc/46Shc-KO大鼠缺乏骨骼肌纤维萎缩和坐骨神经异常的情况，我们认为p52Shc/46Shc-KO大鼠步态受损可能是由于主动肌肉向脑运动中枢的感觉反馈所致。某些心肌纤维中缺乏抗肌营养不良蛋白反映了扩张型心肌病造成的损害。由于只有p52Shc基因敲除的大鼠没有表现出p52Shc/p46Shc-KO的表型，因此p46Shc基因缺失很可能是导致运动异常的原因。我们的数据表明，46Shc在步态调节中的作用是以前未知的。
The ubiquitously expressed adaptor protein Shc exists in three isoforms p46Shc, p52Shc, and p66Shc, which execute distinctly different actions in cells. The role of p46Shc is insufficiently studied, and the purpose of this study was to further investigate its functional significance. We developed unique rat mutants lacking p52Shc and p46Shc isoforms (p52Shc/46Shc-KO) and carried out histological analysis of skeletal and cardiac muscle of parental and genetically modified rats with impaired gait. p52Shc/46Shc-KO rats demonstrate severe functional abnormalities associated with impaired gait. Our analysis of p52Shc/46Shc-KO rat axons and myelin sheets in cross-sections of the sciatic nerve revealed the presence of significant anomalies. Based on the lack of skeletal muscle fiber atrophy and the presence of sciatic nerve abnormalities, we suggest that the impaired gait in p52Shc/46Shc-KO rats might be due to the sensory feedback from active muscle to the brain locomotor centers. The lack of dystrophin in some heart muscle fibers reflects damage due to dilated cardiomyopathy. Since rats with only p52Shc knockout do not display the phenotype of p52Shc/p46Shc-KO, abnormal locomotion is likely to be caused by p46Shc deletion. Our data suggest a previously unknown role of 46Shc actions and signaling in regulation of gait.
登录
查看更多内容
影响因子：
3.7
作者：
Prado FP;Dos Santos DO;Blefari V;Silva CA;Machado J;Kettelhut IDC;Ramos SG;Baruffi MD;Salgado HC;Prado CM
通讯作者：
Prado CM
影响因子：
56.9
作者：
Hardy, W. Rod;Li, Lingying;Pawson, Tony
通讯作者：
Pawson, Tony
影响因子：
7.4
作者：
Wright, Kevin D.;Miller, Bradley S.;Sorokin, Andrey
通讯作者：
Sorokin, Andrey
影响因子：
8.3
作者：
Fehrenbach，Daniel J.;Abais-Battad，Justine M.;Mattson，David L.
通讯作者：
Mattson，David L.
影响因子：
7.8
作者：
Jiang, XG;Edstrom, E;Ulfhake, B
通讯作者：
Ulfhake, B