Molecular Mechanisms of Thalamocortical Development

丘脑皮质发育的分子机制

• 批准号: 7170055
• 负责人: NOELLE D DWYER
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7170055
• 关键词: Architecture; Axon; Brain; Caenorhabditis elegans; Candidate Disease Gene; Cerebral cortex; Defect; Development; Doctor of Philosophy; Embryo; Epilepsy; Exons; Generations; Genes; Genetic; Genetic Screening; Goals; Imagery; Invertebrates; Label; Laboratories; LacZ Genes; Maps; Mediating; Membrane; Mental Retardation; Methods; Molecular; Mus; Mutagenesis; Mutant Strains Mice; Mutation; Neuroanatomy; Neurons; Neurosciences; Pathway interactions; Perception; Phenotype; Process; Proteins; Recovery; Reporter; Resolution; Rodent; Schizophrenia; Screening procedure; Slice; Staging; Standards of Weights and Measures; System; Techniques; Thalamic structure; Training; Work; axon guidance; day; interest; medical schools; motor control; mutant; nematode genetics; nervous system disorder; novel; skills; tau Proteins; tool

DESCRIPTION (provided by applicant): The cerebral cortex mediates perceptions and motor control by receiving and sending information through the thalamus. Some neurological disorders such as mental retardation, epilepsy, and schizophrenia appear to involve developmental defects in the wiring of the cerebral cortex. Molecular mechanisms of thalamocortical axon (TCA) development will be studied by taking a forward genetics approach. Specific Aim I: To peform a screen for mouse mutants with defects in thalamocortical development, using a specific reporter. The TCA-TLZ (thalamocortical axon-tau-lacZ) reporter line allows visualization of TCAs in whole brains without slicing, and therefore provides a unique tool with which to rapidly screen for defects in thalamocortical development. The reporter line will be mutagenized and the brains of third-generation progeny at embryonic day 18 will be analyzed for defects. Screening embryos will enable recovery of lethal mutations. This reporter will reveal defects in thalamic axon guidance and cortical lamination. Specific Aim Il: To characterize the phenotypes of mutants identified in the screen. Mutant brains will be examined at several developmental stages using the tau-lacZ marker as well as standard neuroanatomical and histological methods to determine the extent and cause of the phenotypes observed. Specific Aim Ill: To positionally clone one or two genes identified in the screen that represent the most interesting phenotypes and novel loci. After high resolution mapping, candidate genes will be examined by expression and sequencing of exons from the mutants to find the mutations. The Candidate has an excellent record so far as a neuroscientist, but wishes to receive additional training in mouse genetics before starting an independent laboratory to study the molecular mechanisms underlying cortical development. In the Ph.D., C. elegans genetics was used to study how neurons target proteins to specific membrane domains. A transition was made to the rodent system to study cortical development using histological and neuroanatomical techniques. To add mouse genetics to the skill set, the candidate has arranged to work jointly with Dr. Christopher Walsh and Dr. David Beier, both at Harvard Medical School. Combining the expertise in mouse genetics with the previous training in mouse neuroanatomy and nematode genetics will significantly add to the Candidate's potential to make a strong impact on the field.

描述(申请人提供)：大脑皮层通过丘脑接收和发送信息来调节感知和运动控制。一些神经疾病，如智力低下、癫痫和精神分裂症，似乎与大脑皮层连接的发育缺陷有关。采用正向遗传学方法研究丘脑皮质轴突发育的分子机制。具体目标一：使用一种特定的报告，对丘脑皮质发育缺陷的小鼠突变进行筛选。TCA-TLZ(丘脑皮质轴突-tau-LacZ)报告线可以在整个大脑中可视化TCA，而无需切片，因此提供了一种独特的工具，可以快速筛选丘脑皮质发育中的缺陷。报道线将被诱变，胚胎第18天的第三代后代的大脑将被分析是否存在缺陷。筛选胚胎将使致命突变的恢复成为可能。这位记者将揭示丘脑轴突引导和皮质分层方面的缺陷。具体目的1：鉴定筛选中发现的突变体的表型。突变的大脑将在几个发育阶段使用tau-lacz标记以及标准的神经解剖学和组织学方法进行检查，以确定观察到的表型的程度和原因。具体目的病症：定位克隆一个或两个在屏幕上识别的代表最有趣的表型和新基因的基因。在高分辨率定位后，将通过对突变体的外显子的表达和测序来检查候选基因，以发现突变。到目前为止，这位候选人作为一名神经学家有着出色的记录，但他希望在成立独立实验室研究大脑皮质发育背后的分子机制之前，接受额外的老鼠遗传学培训。在博士学位中，线虫遗传学被用来研究神经元如何将蛋白质靶向特定的膜域。利用组织学和神经解剖学技术，向啮齿动物系统过渡，以研究皮质发育。为了将老鼠遗传学添加到技能集合中，这位候选人安排与哈佛医学院的克里斯托弗·沃尔什博士和大卫·贝尔博士共同工作。将老鼠遗传学方面的专业知识与之前在老鼠神经解剖学和线虫遗传学方面的培训相结合，将极大地增加候选人在该领域产生重大影响的潜力。