Reticulons 1 and 3 are essential for axonal growth and synaptic maintenance associated with intellectual development.
Reticulons 1 and 3 are essential for axonal growth and synaptic maintenance associated with intellectual development.
复制标题
网状细胞 1 和 3 对于与智力发育相关的轴突生长和突触维持至关重要。
DOI：
10.1093/hmg/ddad085
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发表时间：
2023
影响因子：
3.5
通讯作者：
Yan,Riqiang
中科院分区：
文献类型：
--
作者：
Zhou,John;Shi,Qi;Ge,YingY;He,Wanxia;Hu,Xiangyou;Xia,Weiming;Yan,Riqiang
Reticulon （RTN）蛋白是一类生物化学鉴定的形成管状内质网的蛋白家族，管状内质网是一种亚细胞结构，对囊泡运输和细胞间通讯很重要。在我们最近对同时敲除网状蛋白1 （Rtn1）和rtn3的小鼠的研究中，我们发现Rtn1−/−；Rtn3−/−（简称R1R3dKO）小鼠表现出新生儿死亡率，尽管RTN1或Rtn3单独缺乏的小鼠没有明显的表型。这是第一个在RTN蛋白部分成员缺失的动物中发现早期致命性的病例。新生儿死亡率的完全外显性可归因于多种缺陷，包括横膈膜中发现的受损神经肌肉连接。我们还通过免疫组织化学染色检测到神经丝轻链和神经丝中链抗体，发现轴突生长在区域特异性上明显受损。电镜超微结构检查显示海马突触活动带长度明显减少。通过无偏倚的蛋白质组学分析，机制探索揭示了脆性X智力发育迟滞途径中已知的组分，如FMR1、Staufen2、Cyfip1、Cullin-4B和PDE2a等蛋白的减少。总之，我们的研究结果表明，RTN1和RTN3需要协调中枢神经系统的神经丝组织和完整的突触结构。
Reticulon (RTN) proteins are a family of proteins biochemically identified for shaping tubular endoplasmic reticulum, a subcellular structure important for vesicular transport and cell-to-cell communication. In our recent study of mice with knockout of both reticulon 1 (Rtn1) andRtn3, we discovered thatRtn1−/−;Rtn3−/−(brief as R1R3dKO) mice exhibited neonatal lethality, despite the fact that mice deficient in either RTN1 or RTN3 alone exhibit no discernible phenotypes. This has been the first case to find early lethality in animals with deletion of partial members of RTN proteins. The complete penetrance for neonatal lethality can be attributed to multiple defects including the impaired neuromuscular junction found in the diaphragm. We also observed significantly impaired axonal growth in a regional-specific manner, detected by immunohistochemical staining with antibodies to neurofilament light chain and neurofilament medium chain. Ultrastructural examination by electron microscopy revealed a significant reduction in synaptic active zone length in the hippocampus. Mechanistic exploration by unbiased proteomic assays revealed reduction of proteins such as FMR1, Staufen2, Cyfip1, Cullin-4B and PDE2a, which are known components in the fragile X mental retardation pathway. Together, our results reveal that RTN1 and RTN3 are required to orchestrate neurofilament organization and intact synaptic structure of the central nervous system.