朱伯特综合征基因功能失调对斑马鱼中枢神经系统的共同和独特影响

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Accounts of Chemical Research Pub Date : 2024-11-15 Epub Date: 2024-11-12 DOI:10.1242/bio.060421
Alexandra R Noble, Markus Masek, Claudia Hofmann, Arianna Cuoco, Tamara D S Rusterholz, Hayriye Özkoc, Nadja R Greter, Ian G Phelps, Nikita Vladimirov, Sepp Kollmorgen, Esther Stoeckli, Ruxandra Bachmann-Gagescu
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引用次数: 0

摘要

朱伯特综合征(JBTS)是一种神经发育性纤毛症,由高度特异性的中脑-后脑畸形所定义,可与其他神经系统特征相关联。JBTS 具有显著的遗传异质性,其致病基因超过 40 个,这些基因编码的蛋白质定位于初级纤毛器,初级纤毛器是一种感觉细胞器,在神经发育过程中对信号通路的转导以及其他重要功能至关重要。JBTS 蛋白定位于不同的纤毛亚区,表明其在纤毛生物学中具有不同的功能。目前,还没有统一的病理机制来解释这些不同的原发性纤毛相关蛋白的功能障碍是如何导致这种高度特异性的大脑异常的。为了确定 JBTS 基因功能失调的共同后果,我们使用斑马鱼突变体对 JBTS 致病基因 cc2d2aw38、cep290fh297、inpp5ezh506、talpid3i264 和 togaram1zh510 以及 Bardet-Biedl 综合征致病基因 bbs1k742 进行了转录组分析。我们在这些突变体中没有发现普遍失调的信号通路,但所有突变体都显示出与中枢神经系统功能有关的基因集发生了富集变化。我们发现,JBTS 突变体整个大脑的初级纤毛都发生了改变,但没有显示出异常的大脑形态。然而,行为分析表明,斑马鱼的运动能力减弱,姿势控制能力丧失,这与转录组的结果一起,暗示了神经元活动和/或神经元回路功能的潜在异常。因此,这些斑马鱼模型为研究初级纤毛在神经元功能中的作用提供了独特的机会,而不仅仅是早期的模式化、增殖和分化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system.

Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. To identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2aw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510 and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain but do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation.

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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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