Molecular Mechanisms of Thalamocortical Development

丘脑皮质发育的分子机制

• 批准号: 6832855
• 负责人: NOELLE D DWYER
• 金额: $ 13.06万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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/6832855
• 关键词: axon; cerebral cortex; gene expression; gene mutation; laboratory mouse; molecular cloning; molecular genetics; mutant; neurogenesis; neuronal guidance; phenotype; polymerase chain reaction; postdoctoral investigator; thalamocortical tract

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（由申请人提供）：大脑皮层通过丘脑接收和发送信息来介导感知和运动控制。一些神经系统疾病，如智力低下、癫痫和精神分裂症，似乎与大脑皮层线路的发育缺陷有关。将通过正向遗传学方法研究丘脑皮质轴突（TCA）发育的分子机制。具体目标 I：使用特定的报告基因筛选丘脑皮质发育缺陷的小鼠突变体。 TCA-TLZ（丘脑皮质轴突-tau-lacZ）报告基因线无需切片即可可视化整个大脑中的 TCA，因此提供了一种独特的工具，可用于快速筛查丘脑皮质发育缺陷。报告系将被诱变，并在胚胎第 18 天对第三代后代的大脑进行缺陷分析。筛选胚胎将能够恢复致命突变。本记者将揭示丘脑轴突引导和皮质层压的缺陷。具体目标II：表征筛选中鉴定的突变体的表型。将使用 tau-lacZ 标记以及标准神经解剖学和组织学方法在多个发育阶段对突变大脑进行检查，以确定观察到的表型的程度和原因。 具体目标III：定位克隆在筛选中鉴定的代表最有趣的表型和新基因座的一两个基因。高分辨率绘图后，将通过突变体外显子的表达和测序来检查候选基因，以找到突变。该候选人迄今为止作为一名神经科学家有着出色的记录，但希望在建立一个独立的实验室来研究皮质发育的分子机制之前接受额外的小鼠遗传学培训。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。过渡到啮齿动物系统，利用组织学和神经解剖学技术研究皮质发育。为了将小鼠遗传学添加到技能组合中，候选人已安排与哈佛医学院的克里斯托弗·沃尔什博士和大卫·贝尔博士合作。将小鼠遗传学方面的专业知识与之前在小鼠神经解剖学和线虫遗传学方面的培训相结合，将显着增加候选人在该领域产生强大影响的潜力。