对斑马鱼中 mecp2 功能的行为和转录组分析。

IF 1.6 3区 医学 Q3 GENETICS & HEREDITY
Nicholas J. Santistevan, Colby T. Ford, Cole S. Gilsdorf, Yevgenya Grinblat
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引用次数: 0

摘要

雷特综合征(Rett Syndrome,RTT)是一种以严重认知和运动障碍为特征的人类神经发育障碍性疾病,是由保守的转录调节因子甲基-CpG结合蛋白2(Methyl-CpG-binding protein 2,MECP2)的功能障碍引起的。小鼠 Mecp2 突变体表现出人类 RTT 的主要特征,其遗传分析对于破译 MeCP2 的功能机制至关重要;然而,我们对这些复杂机制的了解还不全面。斑马鱼 mecp2 突变体表现出轻微的行为缺陷,但尚未得到深入分析。在这里,我们结合转录组学和行为学实验,评估了斑马鱼 mecp2 突变体在受精后 5 到 7 天(dpf)的基线和刺激诱发的运动反应和感觉过滤。我们的研究表明,斑马鱼mecp2的功能对于正常的移行运动是必需的,但对于粗大运动、声学惊吓反应和感觉过滤(习惯化和感觉运动门控)则是不可或缺的,并揭示了mecp2在视觉刺激行为反应中之前未知的作用。RNA-seq分析确定了需要mecp2功能才能在4 dpf正确转录的大量基因集,通路分析揭示了斑马鱼和哺乳动物中需要MeCP2功能的几条通路。这些发现表明,MeCP2作为转录调节因子的功能在脊椎动物中是保守的,并支持使用斑马鱼来补充小鼠模型,以阐明这些保守的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Behavioral and transcriptomic analyses of mecp2 function in zebrafish

Behavioral and transcriptomic analyses of mecp2 function in zebrafish

Rett syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here, we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish mecp2 mutants from 5 to 7 days post-fertilization (dpf). We show that zebrafish mecp2 function is required for normal thigmotaxis but is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for mecp2 in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires mecp2 function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2's function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.

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来源期刊
CiteScore
5.90
自引率
7.10%
发文量
40
审稿时长
4-8 weeks
期刊介绍: Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.
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