Molecular Genetics of Early Neurogenesis

早期神经发生的分子遗传学

• 批准号: 7574531
• 负责人: ETHAN BIER
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574531
• 关键词: Address; Applications Grants; Binding; Biological Models; Bone Morphogenetic Proteins; Brain; Cells; Comparative Study; Defect; Developmental Biology; Diffusion; Disease; Dorsal; Drosophila genus; Drug Addiction; Drug abuse; Ectoderm; Embryo; Factor Analysis; Future; Gene Expression; Genes; Genetic Enhancer Element; Grant; Health; Human; Invertebrates; Mediating; Modeling; Molecular Genetics; Mutate; Nervous system structure; Neuroectoderm; Neurons; Orthologous Gene; Oxidative Stress; Pathway interactions; Process; Recycling; Repression; Shapes; Signal Transduction; Source; Staging; Vertebrates; blastomere structure; bone morphogenetic protein receptors; cell fate specification; chordin; dopaminergic neuron; gastrulation; gene function; human disease; in vivo; insight; morphogens; mutant; neuroblast; neurodevelopment; neurogenesis; neuromechanism; neuronal patterning; procollagen C-endopeptidase; programs; relating to nervous system; research study; three dimensional structure

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.

了解早期胚胎神经诱导的机制是一个长期存在的问题 由曼戈尔德和斯佩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已鉴定出内源性神经诱导物质 通过阻断由骨形态发生蛋白（BMP）途径介导的信号传导发挥作用的系统。 BMP信号传导在非神经外胚层中起作用，以抑制定义默认神经外胚层的基因的表达。 命运在神经外胚层中，BMP信号传导的拮抗剂，包括果蝇短原肠胚形成（Sog）， 它的脊椎动物直系同源物Chordin阻断了这一通路，从而允许默认的神经细胞命运程序， 为准虽然现在已经了解了BMP拮抗剂如何介导神经诱导的概述， 几个重要问题仍然存在。这些问题中最重要的是：1）BMP和Sog如何 在快速变化的胚胎细胞场的背景下产生并稳定的形态发生梯度，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细胞相互作用的？ 位置信息的来源，将神经系统细分为三个主要领域， 成神经细胞身份基因的保守序列本补助金申请的总体目标是解决 这些和相关的问题外胚层图案和神经元规格。具体目标是： 1)分析负责创建背侧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领域 拟议的实验对人类健康很重要。首先，神经归纳的过程是共同的 到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， 在人类中发生突变会导致疾病。此外，果蝇大脑中的多巴胺能神经元 同样容易受到氧化应激物质的影响，如人类。因此，我们的比较 细胞命运特化的研究与使用果蝇作为药物成瘾的模型有关。这些 这些研究可为我们日后有关人类疾病和药物滥用的研究提供框架。