Mechanisms of neural patterning and the generation of neural diversity in the brain

大脑中神经模式和神经多样性产生的机制

• 批准号: 10408120
• 负责人: Claude Desplan
• 金额: $ 38.44万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408120
• 关键词: Ablation; Activins; Address; Affect; Alleles; Behavior; Bioinformatics; Biological; Biological Models; Brain; Brain region; Cell division; Cells; Complex; Cues; Data; Daughter; Development; Drosophila genus; Ecdysone; Eye; Feedback; Ganglia; Generations; Genes; Genetic; Genetic Transcription; Human; Image; Immune; Lasers; Learning; Location; Mammals; Maps; Mediating; Memory; Modeling; Molecular; Mothers; Mushroom Bodies; Nature; Neurites; Neurons; Optic Lobe; Organism; Outcome; Pattern; Procedures; Process; Proteins; RNA Interference; RNA-Binding Proteins; Recording of previous events; Regulation; Role; Series; Signal Transduction; Specific qualifier value; Structure; System; Testing; Time; To specify; Vertebrates; Work; activating transcription factor; brain size; cell type; ecdysone receptor; fly; in vivo; mRNA tagging; migration; mutant; neural circuit; neural patterning; neuroblast; neuroepithelium; neurogenesis; neuromechanism; notch protein; protein expression; relating to nervous system; response; retinotopic; single cell mRNA sequencing; single-cell RNA sequencing; stoichiometry; tool; transcription factor; visual information; visual process

Project Summary To investigate the generation of neural diversity, we use the simple brain of Drosophila that has only 100,000 neurons but can support complex behaviors and simple learning. The highly deterministic nature of Drosophila brain development allows us to define general rules that control the generation of neural diversity and are applicable to mammalian development, even when this is further modulated by activity-dependent plasticity. The genetic control of optic lobe development can be investigated in depth thanks to the repetitive nature of the system, where information from the 800 unit-eyes (ommatidia) projects to 800 parallel retinotopic columns that sequentially process the visual information through more than 200 cell types. The generation of neural diversity results from the integration of three mechanisms: (i) ~800 medulla neuroblasts (NBs) are patterned by the sequential expression of temporal transcription factors that generate distinct types of neurons at each temporal window. (ii) NBs produce different neurons depending on their location in the neuroepithelium: Spatial factors locally modify the outcome of the temporal series. (iii) Binary fate choice via Notch signaling further diversifies the two daughters of ganglion mother cells (GMCs) born from each NB division. In contrast, NB transitions in the mushroom body, a brain region involved in learning, are controlled by extrinsic factors, generating fewer neuron types through the use of extremely long lineages. The broad context of this proposal will address how basic principles of neurogenesis explain the vast diversity of neurons in the optic lobes and the restricted diversity in the mushroom body, and will help us understand more complex brain structures and instruct further studies in mammals. We will investigate the mechanisms controlling neurogenesis through 4 aims: Aim 1: Temporal progression of neuroblasts: Timing and transition mechanisms: Temporal patterning is a general mechanism to generate neural diversity in flies and vertebrates. We will identify all the temporal factors and investigate their mode of cross-regulation that controls the timing of transitions. Aim 2. Intrinsic specification of neuroblasts in culture: A given temporal transcription factor appears to control the expression of the next factor in the series and to repress the previous factor to form a transcriptional clock mechanism. We will use live imaging of transcription (MS2 system) and of protein expression in vivo and in cultured NBs to investigate the intrinsic molecular mechanisms controlling the timing of transitions. Aim 3. Specification of multi-columnar neurons: We will investigate how multicolumnar neurons are produced locally in response to spatial factors while innervating the entire retinotopic map. We will also investigate how their cell bodies move to distribute throughout the optic lobe. Aim 4. Extrinsic cues for neuroblast transitions in the mushroom body: The mushroom body NBs have very long lineages but produce a limited number of cell types. We will study how Ecdysone and Activin signaling mediate extrinsic transitions between cell types and how they control gradients of RNA binding proteins acting in neuroblasts.

项目摘要 为了研究神经多样性的产生，我们使用了只有10万个神经元的果蝇的简单大脑 但可以支持复杂行为和简单学习。果蝇大脑的高度确定性性质 开发允许我们定义控制神经多样性的产生的一般规则，并且适用于 哺乳动物的发育，即使这进一步受到依赖活动的可塑性的调节。基因控制 由于该系统的重复性，可以对视叶发育进行深入的研究，其中信息 从800个单位眼(小眼)投射到800个平行的视网膜柱，它们顺序地处理视觉 通过200多种细胞类型提供信息。神经多样性的产生是三者整合的结果 机制：(1)约800个延髓神经母细胞(NBS)是通过时间转录的顺序表达而形成的 在每个时间窗口产生不同类型神经元的因素。(Ii)NBS产生不同的神经元依赖于 关于它们在神经上皮细胞中的位置：空间因素局部地改变了时间序列的结果。(Iii)二进制 通过Notch信号的命运选择进一步使神经节母细胞(GMC)的两个子代多样化 NB分部。相比之下，参与学习的大脑区域蘑菇体中的NB转换受 外在因素，通过使用极长的谱系产生更少的神经元类型。这件事的广泛背景 该提案将阐述神经发生的基本原理如何解释视叶神经元的巨大多样性 以及蘑菇体内有限的多样性，将有助于我们了解更复杂的大脑结构和 指导对哺乳动物的进一步研究。我们将通过四个目标来研究神经发生的控制机制： 目标1：神经母细胞的时间进程：时间和过渡机制：时间模式是一种 苍蝇和脊椎动物产生神经多样性的一般机制。我们将确定所有的时间因素，并 调查他们控制过渡时机的交叉监管模式。 目的2.神经母细胞在培养中的内在特性：一种给定的时间转录因子似乎控制着 表达序列中的下一个因子，并抑制前一个因子以形成转录时钟 机制。我们将使用实时转录成像(MS2系统)和体内和培养的蛋白质表达的成像 NBS来研究控制转变时机的内在分子机制。 目的3.多柱神经元的特性：我们将研究多柱神经元是如何产生的 局部对空间因素的反应，同时支配整个视网膜定位图。我们还将调查他们是如何 细胞体移动，分布在视叶各处。 目的4.蘑菇体中神经母细胞转化的外在线索：蘑菇体NBS具有非常 血统很长，但产生的细胞类型有限。我们将研究蜕皮激素和激活素信号是如何调节的 细胞类型之间的外在转换以及它们如何控制作用于神经母细胞的RNA结合蛋白的梯度。