Genetic and molecular anlaysis of neural development

神经发育的遗传和分子分析

基本信息

批准号：
7330350
负责人：
HOWARD I SIROTKIN
金额：
$ 28.32万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7330350
关键词：
Accounting Address Anterior Biological Assay Cell Transplantation Cells Congenital Abnormality Coupled Defect Development Development, Other Disruption Ectoderm Embryo Embryonic Development Endoderm Enhancers Epidermis Etiology Event Family member Fibroblast Growth Factor Fostering Gastrula Generations Genes Genetic Genetic Screening Germ Layers Haploidy Holoprosencephaly Homeobox Genes Human In Situ Mesoderm Methodology Modeling Molecular Molecular Genetics Morphology Mutation Nervous system structure Numbers Pattern Personal Satisfaction Play Process Protein Overexpression Role Signal Transduction Source Staging Techniques Testing Tissues Vertebrates Zebrafish base cell type chordin developmental disease genetic analysis insight mutant neural plate neurodevelopment neuromechanism novel relating to nervous system research study tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The diversity of cell types within the vertebrate nervous system depends on patterning events that occur at early stages of development. The specification and patterning of neural tissue is closely coupled to the development of the other germ layers. The mesoderm and endoderm are important sources of signals that induce neural tissue and establish asymmetries within the neural plate. In this proposal, we seek to utilize the potent genetic and cellular methodologies available in the zebrafish to study patterning of the neural ectoderm. The zebrafish is well suited to this analysis. Zebrafish embryos are transparent and embryonic development occurs rapidly. These attributes foster detailed observation of normal and aberrant embryonic development. Zebrafish produce large numbers of offspring, which in addition to facilitating phenotypic characterization, enhances genetic analysis. The proposed experiments utilize several well characterized zebrafish mutations to investigate the molecular mechanisms that induce and pattern neural tissue. The general approach is to account for all the signals that generate anterior and posterior neural tissue. Models for both neural induction and patterning will be tested. A genetic screen is proposed to identify novel loci that disrupt anterior neural specification. The screen takes advantage of the ability to generate haploid zebrafish embryos in order to increases the throughput of the screen. There are two components to the screen: a morphology based approach to identify enhancers of a mutation (bozozok) which disrupts anterior neural patterning and an in situ based effort to detect alterations of the expression domains of the phox2a transcription factor. One promising mutation identified in a pilot screen alters anterior neural patterning and will be studied in detail. Because all vertebrates share fundamental similarities in the organization of their nervous systems, understanding the genetic networks that govern neural patterning in zebrafish will provide important insights into development of other species, including humans. Several zebrafish mutations have that disrupt embryonic development have anterior neural defects similar to a common human congenital abnormality, holoprosencephaly, and share similar etiologies. Deciphering the mechanisms of vertebrate axis formation may also provide insight into the causes other human developmental disorders.

描述（由申请人提供）：脊椎动物神经系统中细胞类型的多样性取决于在发育早期阶段发生的模式事件。神经组织的规范和模式与其他细菌层的发展紧密耦合。中胚层和内胚层是诱导神经组织并在神经板中建立不对称的信号的重要来源。在此提案中，我们试图利用斑马鱼中可用的有效遗传和细胞方法来研究神经外胚层的模式。斑马鱼非常适合该分析。斑马鱼胚胎是透明的，胚胎发育迅速发生。这些属性促进了对正常和异常胚胎发育的详细观察。斑马鱼产生大量后代，除了促进表型表征外，还增强了遗传分析。提出的实验利用了几种表征的斑马鱼突变来研究诱导和模拟神经组织的分子机制。一般方法是说明所有产生前神经组织和后神经组织的信号。将测试神经诱导和模式的模型。提出了一个遗传筛查，以识别破坏前神经规范的新基因座。屏幕利用生成单倍体斑马鱼胚胎的能力，以增加屏幕的吞吐量。屏幕上有两个组成部分：基于形态学的方法，用于识别突变的增强子（BOZOZOK），该方法破坏了前神经模式和基于原位的努力，以检测PHOX2A转录因子的表达域的改变。在试验屏幕中确定的一个有希望的突变会改变前神经图案，并将详细研究。由于所有脊椎动物在其神经系统组织中具有基本相似之处，因此了解斑马鱼中神经模式的遗传网络将为包括人类在内的其他物种的发展提供重要的见解。斑马鱼突变的一些破坏胚胎发育的前神经缺陷类似于人类普通的先天性异常，全脑脑，并具有相似的病因。解解脊椎动物轴形成的机制也可能提供有关其他人类发育障碍的洞察力。