THE ROLE OF LHX2 IN CEREBRAL CORTICAL DEVELOPMENT

描述（来自申请人的摘要）：在许多方面，大脑皮层 将我们定义为人类，皮层发育异常导致 一系列毁灭性的神经和神经精神疾病的 大脑皮层的发育依赖于紧密协调的基因表达 这是由转录因子控制的。长期目标是 项目是了解皮质发育的转录控制。 本申请关注Lhx2，这是一种转录因子， 在皮质发育的多个阶段中至关重要。我们重新分析 Lhx2基因敲除小鼠已经确定了Lhx2在模式化和免疫调节中的重要作用。 形成几乎所有的新皮层和海马体。此外，Lhx2是 可能在晚期皮质发育中发挥重要作用， 在现有的淘汰线上进行研究。此应用程序的总体目标是 为了了解Lhx2在早期和晚期皮层神经元的功能， 发展，并开始确定Lhx2遗传层次的组成部分 控制着大脑皮层的模式和形成。 具体目标1将通过进一步表征Lhx2的早期作用， Lhx2基因敲除小鼠。具体目标2将研究骨形态发生 蛋白（BMPS）作为Lhx2的潜在上游调节因子。具体目标3将 通过直接测试一个候选物来搜索Lhx2的下游靶标， 使用Lhx2基因敲除小鼠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 敲除细胞系以破坏有丝分裂后皮质神经元中的Lhx2。这些 实验应该提供深入了解皮层的转录控制， 发育并帮助识别可能与人类发育有关的其他基因 神经和神经精神脑疾病。 申请人是医学博士/博士，在解剖病理学方面获得委员会认证， 神经病理学他获得了神经科学博士学位， 神经胶质细胞发育的转录控制。他的导师是克里斯沃尔什， 他领导着一个资金充足、设备齐全的人类和小鼠大脑皮层开发项目， 遗传学实验室研究职业发展计划包括学习 老鼠转基因技术，在当地一家 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.