Epigenetic control of steroid hormone signaling in axon pruning

大脑回路中产生行为的细胞之间的连接可能会在一生中发生变化，这种现象被称为可塑性。导致大脑可塑性的一种机制包括不同类型的经历，开启和关闭控制脑细胞之间连接的基因(表观遗传学)。这项研究通过制造一种名为Kismet的特定蛋白质来研究一种控制其他基因表达的基因；该团队之前的工作表明，Kismet调节其他基因的活动，这些基因控制着脑细胞如何连接在一起。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，以形成或改变大脑中的连接。这种类型的信息对于更好地理解一生中大脑中发生的自然变化和与疾病相关的变化也将是重要的。该奖项还将通过建立现有的课堂本科生研究经验(CURE)来支持提高本科生的定向研究机会。CURE课程解决了多所大学面临的一个关键问题：容纳大量本科生，这些本科生希望参与本科生研究，但由于师资有限：学生比例有限。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，这项工作将帮助教育机构更好地解决科学教育和培训中的重要教学问题。神经科学的一个主要问题是，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长期变化。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。轴突修剪对于正确消除突触至关重要，这是塑造精确神经回路所必需的。有缺陷的修剪与大脑连通性和行为改变有关。果蝇发育中的蘑菇体(MB)神经元中发生的修剪是发育轴突修剪的主要模式。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，这是细胞自主的、轴突修剪中的限速步骤。果蝇中ECR表达的中断会导致轴突被修剪。研究人员发现，Kis与ECR的顺式调控元件结合，其中Kis需要通过促进H3K36甲基化和H4K16乙酰化来激活ECR转录。此外，他们还表明，Kis蛋白水平本身是由转化生长因子-β信号通路控制的，该信号通路已知促进ECR水平和MB轴突修剪。该奖项将确定KIS如何将转化生长因子-β信号联系起来，以控制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。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.