Drosophila Sensory Neuron Development

描述(申请人提供)：钙粘附素介导的动态调节细胞黏附在神经发育过程中发挥重要作用。我们以果蝇幼虫中央脑的形成为模型系统，研究经典钙粘附素DE-cad和dN-cad的功能。幼虫的大脑最初是由数百个初级(胚胎形成的)神经元组成的皮质，围绕着由这些细胞的轴突和树突形成的内部神经堆。神经胶质细胞在神经堆周围、离散的神经元簇周围以及整个大脑周围形成鞘。随着发育的进行，位于皮质表面的神经母细胞产生次级神经元谱系，这些次级神经元在初级神经元周围层层聚集。次级神经元的轴突延伸短束(PATs)，在大多数情况下，这些轴突停留在形成皮质-神经堆边界的神经胶质鞘处，并在变态过程中才晚些时候分化。次级神经元和轴突以及所有胶质细胞均表达DE-cad。原代神经元普遍表达dN-cad。上一次资助期间收集的证据表明，DE-cad和dN-cad在神经母细胞增殖、神经元在反映细胞出生时间的同心层中的定位、次级轴突导航、皮质-神经桩交界处的轴突停止以及初级和次级轴突的分离中发挥关键作用。我们提出了以下六个具体目标，重点研究钙粘附素在果蝇幼虫大脑发育中的作用。第一个目的是详细研究不同谱系形成的PATP的模式和时间过程，以及与神经堆神经胶质细胞接触的静止生长锥体的特性。目的#2观察神经胶质细胞的发育以及去除神经胶质细胞对幼虫脑发育的影响。目标#3和#4深入探讨DE-cad与作为DE-cad神经发育功能基础的动态细胞骨架之间的相互作用的分子细节，特别侧重于次级神经元“停滞”的轴突与神经胶质细胞之间的相互作用。在目标5中，我们讨论了在大脑发育过程中以互补模式表达两种经典钙粘附素DE-cad和dN-cad的意义。目的#6旨在作为一项先导性研究，分析果蝇非经典钙粘附素在幼虫脑中的表达模式。我们预计，这些拟议目标的结果将广泛应用于神经发育(特别是脊椎动物)，因为形态发生过程之间的高度保守塑造了动物的大脑。

DESCRIPTION (provided by applicant): Dynamically regulated cell adhesion mediated by cadherins plays an important role during neural development. We use the formation of the larval central brain in Drosophila as a model system to investigate the function of the classical cadherins, DE-cad and DN-cad. The larval brain starts out as a cortex of several hundred primary (embryonically formed) neurons surrounding an inner neuropile, formed by axons and dendrites of these cells. Glial cells form sheaths around the neuropile, around discrete clusters of neurons, and around the brain as a whole. As development proceeds, neuroblasts located at the cortex surface produce lineages of secondary neurons that aggregate in layers around the primary neurons. Axons of secondary neurons extend short tracts (PATs) that in most cases arrest at the glial sheath that forms the cortex-neuropile boundary and differentiate only later during metamorphosis. Secondary neurons and axons, as well as all glial cells express DE-cad. Primary neurons globally express DN-cad. Evidence gathered during the previous funding period indicates that DE-cad and DN-cad play a pivotal role in neuroblast proliferation, positioning of neurons in concentric layers that reflect the time of cell birth, secondary axon navigation, axon arrest at the cortex-neuropile interface, and separation of primary from secondary axons. We propose in the following six specific aims which focus on the role of cadherins in Drosophila larval brain development. The first aim is to investigate in detail the pattern and time course of PATs formed by different lineages, and the properties of the stationary growth cones in contact with the neuropile glia. Aim #2 looks at the development of glia and the effect of ablating glia on larval brain development. Aims #3 and #4 go into molecular detail in addressing the interactions between DE-cad and the dynamic cytoskeleton that underlies DE-cad function in neural development, focusing in particular on the interaction between the "stalled" axons of secondary neurons and glia. In Aim #5 we address the significance of having two classical cadherins, DE-cad and DN-cad, expressed in a complementary pattern during brain development. Aim #6 is intended as a pilot study, analyzing the expression patterns of the Drosophila non-classical cadherins in the larval brain. We expect that the results of these proposed aims will apply to neural development widely (in particular to vertebrates) because the high degree of conservation between morphogenetic processes shaping animal brains.