斑马鱼胚胎前脑神经节的形成需要 KLC1 与 CRMP2 结合。

IF 2.7 4区 医学 Q2 DEVELOPMENTAL BIOLOGY
Simo Li, Youjia Guo, Miyuki Takahashi, Hisato Suzuki, Kenjiro Kosaki, Toshio Ohshima
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引用次数: 0

摘要

连接左右大脑半球的胼胝体(CC)、前裂(AC)和视后裂(POC)的形成对大脑功能至关重要。根据小鼠的基因敲除研究和斑马鱼的基因敲除/基因敲除研究,塌缩素反应介导蛋白 2(CRMP2)被认为与支配这种形成的机制有关。此前,我们报道了两例非同义CRMP2变体,分别为S14R和R565C置换。其中,R565C置换(p.R565C)是由新型CRMP2突变c.1693C > T引起的,患者表现为智力障碍并伴有CC发育不全。本研究证明,crmp2 mRNA能挽救crmp2-敲除斑马鱼的AC和POC形成,而R566C突变的mRNA则不能。斑马鱼 CRMP2 R566C 与人类 CRMP2 R565C 相对应。转染培养细胞的进一步实验表明,R566C 突变的 CRMP2 无法与驱动蛋白轻链 1(KLC1)结合。在斑马鱼体内敲除 klc1a 会导致 AC 和 POC 形成缺陷,从而揭示了 CRMP2 与 KLC1 的基因相互作用。这些发现表明,CRMP2 R566C突变体无法与KLC1结合,从而阻碍了轴突的伸长,导致斑马鱼AC和POC形成缺陷以及人类CC形成缺陷。我们的研究强调了CRMP2和KLC1之间的相互作用在前脑神经突起形成过程中的重要性,揭示了与CRMP2突变相关的人类神经发育异常的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Forebrain commissure formation in zebrafish embryo requires the binding of KLC1 to CRMP2

Formation of the corpus callosum (CC), anterior commissure (AC), and postoptic commissure (POC), connecting the left and right cerebral hemispheres, is crucial for cerebral functioning. Collapsin response mediator protein 2 (CRMP2) has been suggested to be associated with the mechanisms governing this formation, based on knockout studies in mice and knockdown/knockout studies in zebrafish. Previously, we reported two cases of non-synonymous CRMP2 variants with S14R and R565C substitutions. Among the, the R565C substitution (p.R565C) was caused by the novel CRMP2 mutation c.1693C > T, and the patient presented with intellectual disability accompanied by CC hypoplasia. In this study, we demonstrate that crmp2 mRNA could rescue AC and POC formation in crmp2-knockdown zebrafish, whereas the mRNA with the R566C mutation could not. Zebrafish CRMP2 R566C corresponds to human CRMP2 R565C. Further experiments with transfected cultured cells indicated that CRMP2 with the R566C mutation could not bind to kinesin light chain 1 (KLC1). Knockdown of klc1a in zebrafish resulted in defective AC and POC formation, revealing a genetic interaction with crmp2. These findings suggest that the CRMP2 R566C mutant fails to bind to KLC1, preventing axonal elongation and leading to defective AC and POC formation in zebrafish and CC formation defects in humans. Our study highlights the importance of the interaction between CRMP2 and KLC1 in the formation of the forebrain commissures, revealing a novel mechanism associated with CRMP2 mutations underlying human neurodevelopmental abnormalities.

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来源期刊
Developmental Neurobiology
Developmental Neurobiology 生物-发育生物学
CiteScore
6.50
自引率
0.00%
发文量
45
审稿时长
4-8 weeks
期刊介绍: Developmental Neurobiology (previously the Journal of Neurobiology ) publishes original research articles on development, regeneration, repair and plasticity of the nervous system and on the ontogeny of behavior. High quality contributions in these areas are solicited, with an emphasis on experimental as opposed to purely descriptive work. The Journal also will consider manuscripts reporting novel approaches and techniques for the study of the development of the nervous system as well as occasional special issues on topics of significant current interest. We welcome suggestions on possible topics from our readers.
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