Linking neuronal identity transcription factors to neural circuit establishment and maintenance

将神经元身份转录因子与神经回路的建立和维护联系起来

• 批准号: 10386149
• 负责人: Kristen M Lee
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386149
• 关键词: Address; Adult; Affect; Aging; Attention deficit hyperactivity disorder; Axon; Biological Assay; Biological Metamorphosis; Brain; Caenorhabditis elegans; Cell surface; Cognition; Complex; Coupled; Data; Defect; Dendrites; Development; Developmental Process; Drosophila genus; Drug abuse; Embryo; Esthesia; Event; Foundations; Gene Expression; Gilles de la Tourette syndrome; Goals; Hormones; Individual; Interneurons; Larva; Lead; Learning; Life; Link; Locomotion; Maintenance; Mammals; Membrane; Mental disorders; Modeling; Molecular; Molecular Profiling; Morphology; Motor; Movement; Neuraxis; Neurites; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Neurotransmitters; Outcome; Phenotype; Property; Puberty; RNA interference screen; Risk; Role; Schizophrenia; Shapes; Sleep; Specific qualifier value; Synapses; System; Testing; Therapeutic; Walking; Work; autism spectrum disorder; behavioral phenotyping; experimental study; fly; homeodomain; interest; molecular marker; neural circuit; neural patterning; neurogenesis; neuromechanism; optogenetics; relating to nervous system; response; transcription factor

PROJECT SUMMARY/ABSTRACT Neuronal identity is generated during development, with identity characterized by neuron-specific gene expression, axon/dendrite morphology, and connectivity. Homeodomain transcription factors (TFs) are required for establishing gene expression and neuronal morphology, but whether they are required for neuronal connectivity is unknown. Understanding the developmental processes generating neuronal identity in general, and connectivity in particular, is essential for understanding brain assembly and function. An attractive model is that homeodomain TFs – known to regulate neuronal molecular and morphological identity – also facilitate the expression of cell surface molecules that allow the formation of highly-specific neural connections. Connections between individual neurons contribute to neural circuits, which allow sensation, movement and cognition. Proper circuit function throughout life relies on continued circuit remodeling, both synaptically and structurally. Interestingly, homeodomain TFs are expressed in adult neurons, well after neuronal identity has been established. I hypothesize that the homeodomain TFs are required for neural circuit establishment and maintenance throughout life. To test this, I have performed a systematic screen for homeodomain TFs required for the function of a locomotor neural circuit in Drosophila, the Moonwalker Descending Neuron (MDN) and Pair1 circuit. I have identified 16 homeodomain TFs required for MDN or Pair1 optogenetic induced locomotion. In Aim 1, I will test how these 16 homeodomain TFs contribute to neuronal identity by assaying molecular identity, axon/dendrite morphology, and connectivity. My pilot experiments have already shown that the homeodomain TF Bicoid is required for connectivity but not molecular identity or morphology. In Aim 2, I will utilize how the MDN-Pair1 circuit is remodeled during Drosophila metamorphosis and persists in the adult fly. I will assay whether the TFs required for establishing MDN-Pair1 connectivity are also required for maintaining the MDN-Pair1 circuit throughout adulthood. My pilot data shows that Bicoid is also expressed in the adult Pair1 neurons. My overarching goal is to advance the understanding of how developmental mechanisms, specifically homeodomain TFs, establish circuits during development and maintain circuits after periods of plasticity/remodeling. Given that fly and mammalian neurogenesis share many conserved features, that homeodomain TFs are highly conserved between species, and that aberrant neural circuits have been implicated in neurodevelopmental and psychiatric disorders, we expect our results to be both translatable and therapeutically relevant.

项目摘要/摘要 神经元身份是在发育过程中产生的，具有神经元特异性的特征 基因表达，轴突/树突形态和连通性。同源域转录因子 （TF）建立基因表达和神经元形态是必需的，但是它们是否是 神经元连通性所需的所需。了解发展过程 一般产生神经元身份，尤其是连通性，对于理解至关重要 大脑组装和功能。一个有吸引力的模型是副域TFS - 已知可以调节 神经元分子和形态学身份 - 也有助于细胞表面的表达 允许形成高度特异性神经连接的分子。之间的连接 单个神经元有助于神经元电路，从而可以感觉，运动和认知。 在整个生命中，适当的电路功能都取决于续电路重塑，无论是突触和 结构上。有趣的是，同源域TF在成年神经元中表达，神经元之后 已经建立了身份。我假设同源域TF是神经需要的 一生的电路建立和维护。为了测试这一点，我进行了 具有运动神经电路功能所需的同源域TF的系统屏幕 果蝇，月球漫步者降序神经元（MDN）和Pair1电路。我已经确定了16 MDN或PAIR1光遗传诱导的运动所需的同源域TF。在AIM 1中，我将测试 这16个同源域TF如何通过测定分子身份来促进神经元认同 轴突/树突形态和连通性。我的飞行员实验已经表明 同源域TF双粒是连通性所必需的，而不是分子身份或形态。目标 2，我将利用果蝇变态过程中如何重塑MDN-PAIR1电路并持续存在 在成年苍蝇中。我将测定建立MDN-PAIR1连接所需的TFS是否也是 整个成年期维持MDN-PAIR1电路所必需的。我的飞行员数据表明​​双子 也在成人Pair1神经元中表达。我的总体目标是提高对 如何在期间建立电路的发展机制，特别是同源域TF 可塑性/重塑后，开发和维护电路。鉴于那苍蝇和 哺乳动物神经发生具有许多保守的特征，同源域TF非常高 物种之间的保守和异常的神经回路已与 神经发育和精神疾病，我们希望我们的结果既可以翻译，又 在治疗上相关。