THE ROLE OF LHX2 IN CEREBRAL CORTICAL DEVELOPMENT

描述(摘自申请者的摘要)：在许多方面，大脑皮质 将我们定义为人类，皮质发育的异常会导致 一些毁灭性的神经学和神经精神障碍。这个 大脑皮层的发育依赖于紧密协调的基因表达 这是由转录因子引导的。这样做的长期目标是 这个项目是为了了解大脑皮质发育的转录控制。 这个应用程序关注的是LHX2，一种似乎是 在大脑皮层发育的多个阶段是必不可少的。我们对新世纪的重新分析 LHX2基因敲除小鼠已经确定了LHX2在图案形成和 形成几乎所有的新皮质和海马体。此外，LHX2是 可能在皮质发育后期发挥重要作用，但不可能 在现有的淘汰线上学习。此应用程序的总体目标是 了解LHX2在大脑皮层早期和晚期的功能 开发，并开始确定LHX2遗传层次的组成部分 它控制着大脑皮层的图案和形成。 具体目标1将通过进一步描述LHX2的特征来解决LHX2的早期作用 LHX2基因敲除鼠标。特殊目标2将研究骨形态发生 作为LHX2潜在上游调节因子的蛋白质(BMPS)。具体目标3将 通过直接测试一个候选和搜索LHX2的下游靶点 使用LHX2基因敲除鼠标和微阵列分析寻找其他基因。 具体目标4将通过设计一个有条件的 干扰有丝分裂后皮质神经元中LHX2的基因敲除系。这些 实验应该提供对皮层转录控制的洞察力 并帮助确定其他可能与人类 神经学和神经精神性脑部疾病。 申请人为医学博士/博士，拥有解剖病理学委员会认证，并 神经病理学。他获得了神经科学研究的博士学位。 发育中的神经胶质细胞的转录调控。他的导师是克里斯·沃尔什， 世卫组织领导着资金雄厚、装备精良的人类和小鼠皮质发育和 遗传学实验室。研究人员的职业发展计划包括学习 老鼠转基因技术，在当地一家经营一家 转基因核心设施。

DESCRIPTION (From the Applicant's Abstract): In many ways the cerebral cortex defines us as human beings, and abnormalities of cortical development result in a number of devastating neurologic and neuropsychiatric disorders. The development of cerebral cortex depends on tightly coordinated gene expression that is directed by transcription factors. The long-term objective of this project is to understand the transcriptional control of cortical development. This application focuses on Lhx2, a transcription factor that appears to be essential in multiple stages of cortical development. Our re-analysis of the Lhx2 knockout mouse has identified essential roles for Lhx2 in patterning and formation of virtually all of neocortex and hippocampus. In addition, Lhx2 is likely to have essential roles in late cortical development that cannot be studied in the existing knockout line. The overall goal of this application is to understand the functions of Lhx2 during both early and late cortical development, and to begin identifying components of the Lhx2 genetic hierarchy that controls patterning and formation of the cerebral cortex. Specific aim 1 will address the early roles of Lhx2 by further characterizing the Lhx2 knockout mouse. Specific aim 2 will study the bone morphogenetic proteins (BMPS) as potential upstream regulators of Lhx2. Specific aim 3 will search for downstream targets of Lhx2 by directly testing one candidate and searching for others using the Lhx2 knockout mouse and microarray analysis. Specific aim 4 will address the late roles of Lhx2 by engineering a conditional knockout line to disrupt Lhx2 in postmitotic cortical neurons. These experiments should provide insight into the transcriptional control of cortical development and help identify other genes that may be responsible for human neurologic and neuropsychiatric brain disorders. The applicant is an MD/PhD who is board-certified in anatomic pathology and neuropathology. He earned his doctoral degree in neuroscience studying transcriptional control of developing glial cells. His mentor is Chris Walsh, who heads a well-funded well-equipped human and mouse cortical development and genetics laboratory. The research career development plan includes learning mouse transgenic technology, with the help of a consultant who runs a local transgenic core facility.