Molecular Genetics of Early Neurogenesis

了解早期胚胎的神经诱导机制是一个长期存在的问题 由曼戈尔德和斯普曼的开创性实验定义的发育生物学。在过去的十年里， 在脊椎动物和无脊椎动物模型中都发现了内源性神经诱导物质 通过阻断骨形态发生蛋白(BMP)途径介导的信号而发挥作用的系统。 BMP信号作用于非神经性外胚层，抑制决定缺省神经细胞的基因表达 命运。在神经外胚层，BMP信号的拮抗剂，包括果蝇短原肠形成(SOG)，以及 它的脊椎动物同源蛋白，阻断了这一途径，从而允许默认的神经细胞命运程序 赢定了。尽管BMP拮抗剂如何介导神经诱导的轮廓现在已经被理解， 有几个重要的问题仍然存在。这些问题中最重要的是：1)BMP和SOG如何 在细胞胚胎场迅速变化的背景下创建和稳定的形态梯度，以及 2)BMP活性梯度是如何在神经外胚层中形成的，以及它是如何与其他 位置信息来源将神经系统细分为三个主要区域，表达 神经母细胞识别基因的保守集合？这项赠款申请的总体目标是解决 这些问题和相关的外胚层模式和神经元的规格。具体目标是： 1)分析造成背部BMP活性梯度的机制 2)分析DPP如何将神经外胚层细分为三个区域 拟议中的实验对人类健康很重要。首先，神经诱导的过程是常见的 脊椎动物和无脊椎动物。因此，从拟议的实验中获得的见解将是 适用于人类神经发育的早期阶段。第二，与此相关的几个基因的缺陷 这一过程在人类身上发生突变时会导致疾病。此外，果蝇大脑中的多巴胺能神经元 同样容易受到引起氧化应激的物质的影响，就像人类一样。因此，我们的比较 细胞命运指定的研究与使用果蝇作为药物成瘾的模型有关。这些 研究可能会为我们未来与人类疾病和药物滥用相关的研究提供框架。

Understanding the mechanism of neural induction in early embryos is a long standing problem in developmental biology defined by the pioneering experiments of Mangold and Spemann. In the last decade, endogenous neural inducing substances have been identified in both vertebrate and invertebrate model systems which function by blocking signaling mediated by the Bone Morphogenetic Protein (BMP)pathway. BMP signaling acts in the non-neural ectoderm to suppress expression of genes defining the default neural fate. In the neuroectoderm, antagonists of BMP signaling, including Drosophila Short gastrulation (Sog), and its vertebrate ortholog Chordin, block this pathway thereby permitting the default neural cell fate program to prevail. Although the outline of how neural induction is mediated by BMP antagonists is now understood, several important questions remain. Foremost among these issues are: 1) how are BMP and Sog morphogen gradients created and stabilized in the context of a rapidly changing embryonic field of cells, and 2) how does a gradient of BMP activity form in the neuroectoderm and how does it interact with other sources of positional information to subdivide the nervous system into three primary domains expressing conserved sets of neuroblast identity genes? The overall objective of this grant application is to address these and related questions in ectodermal patterning and neuronal specification. The Specific Aims are: 1) Analyze mechanisms responsible for creating a dorsal BMP activity gradient 2) Analyze how Dpp contributes to subdividing the neuroectoderm into three territories The proposed experiments are important to human health. First, the process of neural induction is common to vertebrates and invertebrates. Consequently, insights gained from the proposed experiments will be applicable to early stages of human neural development. Second, defects in several genes involved in this process cause disease when mutated in humans. Also, dopaminergic neurons in the brain of Drosophila are similarly vulnerable to substances causing oxidative stress, as in humans. Therefore, our comparative studies in cell fate specification are relevant to using Drosophila as a model for drug addiction. These studies may provide the framework for our future studies relevant to human disease and drug abuse.