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.

项目概要/摘要 神经元身份是在发育过程中产生的，其特征在于神经元特异性 基因表达、轴突/树突形态和连接性。同源域转录因子 （TF）是建立基因表达和神经元形态所必需的，但它们是否是 神经元连接所需的物质尚不清楚。了解发展过程 产生一般的神经元身份，特别是连接性，对于理解至关重要 大脑的组装和功能。一个有吸引力的模型是同源域 TF——众所周知，它可以调节 神经元分子和形态特征——也促进细胞表面的表达 允许形成高度特异性神经连接的分子。之间的连接 单个神经元构成神经回路，从而实现感觉、运动和认知。 整个生命过程中正确的电路功能依赖于持续的电路重塑，无论是突触还是 结构上。有趣的是，同源结构域 TF 在成年神经元中表达，远远晚于神经元的表达。 身份已确定。我假设同源结构域 TF 是神经网络所必需的 电路的建立和整个生命周期的维护。为了测试这一点，我执行了 系统筛选运动神经回路功能所需的同源域转录因子 果蝇、月球行者下降神经元 (MDN) 和 Pair1 电路。我已经确定了16个 MDN 或 Pair1 光遗传学诱导运动所需的同源域 TF。在目标 1 中，我将测试 这 16 个同源域 TF 如何通过分析分子身份来促进神经元身份， 轴突/树突形态和连接性。我的试点实验已经表明 连接需要同源结构域 TF Bicoid，但分子身份或形态不需要。瞄准 2，我将利用 MDN-Pair1 电路在果蝇变态过程中如何重塑并持续存在 在成年蝇中。我将测试建立 MDN-Pair1 连接所需的 TF 是否也是 整个成年期维持 MDN-Pair1 电路所需的。我的试验数据显示 Bicoid 也在成人 Pair1 神经元中表达。我的首要目标是增进对 发育机制，特别是同源结构域转录因子，如何在发育过程中建立电路 在可塑性/重塑期后开发和维护电路。鉴于那只苍蝇和 哺乳动物的神经发生有许多保守的特征，即同源结构域 TF 高度 物种间保守，并且异常的神经回路与 神经发育和精神疾病，我们希望我们的结果既可以翻译，也可以 治疗相关。