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Epigenetic control of steroid hormone signaling in axon pruning

轴突修剪中类固醇激素信号的表观遗传控制

基本信息

批准号：
1856439
负责人：
Jennifer Stanford
金额：
$ 131万
依托单位：
Drexel University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1856439&HistoricalAwards=false
关键词：
Epigenetic control steroid hormone signaling

项目摘要

The connections between cells in brain circuits that produce behavior can change throughout life, a phenomenon referred to as plasticity. One mechanism contributing to brain plasticity consists of different types of experiences turning genes that control the connections between brain cells on and off (epigenetics). This research examines one gene that controls the expression of other genes by making a specific protein called Kismet; the team's previous work has shown that Kismet regulates the activity of other genes that control how brain cells are wired together. By more fully understanding the specific ways that Kismet regulates brain plasticity, the investigators hope to better understand how different experiential factors (such as social interaction) and biological factors (such as aging) affect gene expression to form or alter connections in the brain. This type of information will also be important for better understanding natural and disease-related changes that occur in the brain throughout life. This award will also support the enhancement of directed research opportunities for undergraduate students by building upon an existing Classroom Undergraduate Research Experience (CURE). The CURE class addresses a critical problem that multiple universities face: accommodating the large number of undergraduate students who want to participate in undergraduate research but cannot due to limited faculty: student ratios. By further improving the provision of significant research experiences for large numbers of undergraduates in a classroom setting, this work will help educational institutions to better addresses important pedagogical concerns in science education and training.A major question in neuroscience is how signaling cascades integrate experiential, environmental and/or internal cues to form long-lasting changes in gene expression required to form precise neural circuits. This award will address this question by examining the epigenetic mechanisms that link steroid hormone receptor gene expression to axon pruning in the developing brain. Axon pruning is critical for proper synapse elimination required to sculpt precise neural circuits. Defective pruning is associated with altered brain connectivity and behavior. A premier model of developmental axon pruning is the pruning that occurs in the developing mushroom body (MB) neurons in the fruit fly Drosophila melanogaster. This pruning requires precise control of the expression of the steroid hormone receptor Ecdysone Receptor (EcR) in MB neurons, which is a cell-autonomous, rate-limiting step in axon pruning. Disruption of EcR expression in Drosophila leads to unpruned axons. The investigators have shown that Kis binds cis regulatory elements of EcR, where Kis is required to activate EcR transcription by promoting H3K36 methylation and H4K16 acetylation. Further, they have shown that Kis protein levels are themselves controlled by the TGF-Beta signaling pathway, which is known to promote EcR levels and MB axon pruning. This award will determine how Kis links TGF-Beta signaling to control EcR transcription and MB pruning. It will also determine how Kis promotes epigenetic changes to control EcR transcription and MB pruning.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

大脑回路中产生行为的细胞之间的连接可以在一生中改变，这种现象被称为可塑性。一种促进大脑可塑性的机制由不同类型的经历组成，这些经历使控制脑细胞之间连接的基因开启和关闭（表观遗传学）。这项研究检查了一种基因，这种基因通过制造一种叫做Kismet的特殊蛋白质来控制其他基因的表达；该团队之前的工作表明，Kismet调节了控制脑细胞连接方式的其他基因的活动。通过更全面地了解Kismet调节大脑可塑性的具体方式，研究人员希望更好地了解不同的经验因素（如社会互动）和生物因素（如衰老）如何影响基因表达，从而形成或改变大脑中的连接。这类信息对于更好地理解大脑在一生中发生的自然和疾病相关变化也很重要。该奖项还将通过建立现有的课堂本科生研究经验（CURE）来支持本科生定向研究机会的增强。CURE课程解决了许多大学面临的一个关键问题：容纳大量希望参与本科研究但由于教师和学生比例有限而无法参与的本科生。通过进一步改善在课堂环境中为大量本科生提供重要的研究经验，这项工作将有助于教育机构更好地解决科学教育和培训中重要的教学问题。神经科学中的一个主要问题是信号级联如何整合经验、环境和/或内部线索，形成形成精确神经回路所需的基因表达的持久变化。该奖项将通过研究类固醇激素受体基因表达与发育中的大脑轴突修剪之间的表观遗传机制来解决这个问题。轴突修剪是关键的正确的突触消除需要雕刻精确的神经回路。有缺陷的修剪与大脑连接和行为的改变有关。发育轴突修剪的一个主要模型是发生在果蝇发育中的蘑菇体（MB）神经元上的修剪。这种修剪需要精确控制MB神经元中类固醇激素受体蜕皮激素受体（EcR）的表达，这是轴突修剪中细胞自主的限速步骤。果蝇中EcR表达的破坏导致轴突未修剪。研究人员已经表明，Kis结合EcR的顺式调控元件，其中Kis通过促进H3K36甲基化和H4K16乙酰化来激活EcR转录。此外，他们还发现Kis蛋白水平本身受tgf - β信号通路控制，而tgf - β信号通路可促进EcR水平和MB轴突修剪。该合同将确定Kis如何连接tgf - β信号来控制EcR转录和MB修剪。它还将确定Kis如何促进表观遗传变化以控制EcR转录和MB修剪。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。