Regulation of Laminar Fate in Cerebral Cortex

描述（由申请人提供）：大脑皮层是具有关键运动、感觉、语言和认知功能的高级大脑区域。皮质发育异常可导致神经系统和精神疾病，包括癫痫、智力迟钝和自闭症。在这个独立科学家奖的提案中，将研究控制皮层神经元（包括分子表达）的层状命运的机制。Hevner博士是一位研究大脑皮层发育的神经病理学家/神经科学家。他的近期职业目标是：1）建立一个强有力的独立研究计划，2）通过与更资深的专家（大卫普莱斯博士）合作，扩大他实验室的技术库，3）通过加强与华盛顿大学同事的互动来提高生产力，以及4）继续提高他作为神经病理学家和教师的技能。他的长期职业目标是将基础研究的进展应用于对影响大脑皮层的疾病的理解、诊断和治疗。Hevner博士的实验室和办公室位于Harborview医学中心（HMC）一个现代化的、设备齐全的研究设施内，该中心靠近华盛顿大学（UW）的主校区。HMC和UW支持一个由有成就的发展神经科学家组成的大型社区，并提供丰富的课程，研讨会，期刊俱乐部和演讲。先前的研究表明，皮层的每一层都包含投射神经元，这些神经元通过细胞大小、轴突连接和分子表达的相似性而相互关联。这些特性的表达与细胞出生日期密切相关，但机制尚不清楚，有些特性可能在有丝分裂后受到调控。这一提议检验了细胞层特异性分子表达可以在有丝分裂后调节的假设。将新产生的有丝分裂后神经元移植到对照（相同年龄）胚胎、异时（不同年龄）胚胎或Rein突变胚胎的皮质中，所述胚胎缺乏Reelin并且具有混乱的皮质。然后使用一组层特异性标记物检查移植细胞的分子表达。如果在异时或Rein突变的皮质中观察到分子命运，这将表明层命运的某些方面可以在有丝分裂后进行调节。

DESCRIPTION (provided by applicant): The cerebral cortex is a higher brain region with critical motor, sensory, language, and cognitive functions. Developmental abnormalities of the cortex can cause neurologic and psychiatric diseases including epilepsy, mental retardation, and autism. In this proposal for an Independent Scientist Award, the mechanisms that control the laminar fates of cortical neurons (including molecular expression) will be studied. Dr. Hevner is a neuropathologist/neuroscientist who studies cortical development. His immediate career goals are to: 1) establish a vigorous independent research program, 2) expand the repertoire of techniques in his laboratory through collaboration with a more senior expert (Dr. David Price), 3) to increase productivity through enhanced interactions with colleagues at the University of Washington, and 4) to continue enhancing his skills as a neuropathologist and teacher. His long-term career objective is to apply advances in basic research to the understanding, diagnosis, and treatment of diseases affecting the cortex. Dr. Hevner's laboratory and office are located in a modern, well-equipped research facility with animal housing at the Harborview Medical Center (HMC), near the main campus of the University of Washington (UW). HMC and UW support a large community of accomplished developmental neuroscientists, and offer an abundance of available courses, seminars, journal clubs, and presentations. Previous studies have shown that each layer of the cortex contains projection neurons related by similarities of cell size, axonal connections, and molecular expression. The expression of these properties is closely correlated with cell birth date, but mechanisms are unclear and some properties may be regulated post-mitotically. This proposal tests the hypothesis that layer-specific molecular expression can be regulated post-mitotically. Newly generated post-mitotic neurons will be transplanted into the cortex of control (same age) embryos, heterochronic (different age) embryos, or Rein mutant embryos, which lack Reelin and have a disorganized cortex. The molecular expression of transplanted cells will then be examined using a panel of layer-specific markers. If molecular fates are aEered in heterochronic or Rein mutant cortex, this would suggest that certain aspects of laminar fate can be regulated post-mitotically.