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

项目摘要 为了研究神经多样性的产生，我们使用了果蝇的简单大脑，它只有10万个神经元。 但可以支持复杂的行为和简单的学习。果蝇大脑的高度决定性 发展使我们能够定义控制神经多样性产生的一般规则，并适用于 哺乳动物的发展，即使这是进一步调制的活动依赖可塑性。遗传控制 由于系统的重复性，可以深入研究视叶发育的过程， 从800个单位眼（小眼）投射到800个平行的视网膜定位柱， 超过200种细胞类型的信息。神经多样性的产生源于三个因素的整合。 机制：（i）~800个髓质成神经细胞（NB）通过时序转录的顺序表达形成模式， 这些因素在每个时间窗口产生不同类型的神经元。(ii)NB产生不同的神经元， 空间因素局部地改变时间序列的结果。(iii)二进制 通过Notch信号传导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部门。相比之下，蘑菇体（一个参与学习的大脑区域）的NB转换是由 外在因素，通过使用极长的谱系产生较少的神经元类型。这件事的大背景 这项提案将讨论神经发生的基本原理如何解释视叶神经元的巨大多样性 以及蘑菇体中有限的多样性，这将帮助我们了解更复杂的大脑结构， 指导进一步的哺乳动物研究。我们将通过4个目标研究控制神经发生的机制： 目的1：成神经细胞的时间进程：时间和转换机制：时间模式是一个重要的机制。 一般机制产生神经多样性在苍蝇和脊椎动物。我们将确定所有的时间因素， 研究它们控制转变时间的交叉调节模式。 目标2.培养中神经母细胞的内在特化：一种特定的时间转录因子似乎控制着 在该系列中的下一个因子的表达和抑制前一个因子以形成转录时钟 机制我们将使用转录（MS 2系统）和蛋白质表达在体内和培养 NB研究控制转换时间的内在分子机制。 目标3：多柱状神经元的特化：我们将研究多柱状神经元是如何产生的 局部地响应于空间因素，同时神经支配整个视网膜定位图。我们还将调查他们如何 细胞体移动以分布在整个视叶中。 目标4。蘑菇体中神经母细胞转变的外在线索：蘑菇体NB具有非常高的 长谱系，但产生有限数量的细胞类型。我们将研究蜕皮激素和激活素信号传导如何介导 细胞类型之间的外在转换以及它们如何控制成神经细胞中RNA结合蛋白的梯度。

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.