Regulation of Laminar Fate in Cerebral Cortex

描述（由申请人提供）：大脑皮层是大脑的高级区域，具有关键的运动、感觉、语言和认知功能。大脑皮层发育异常会导致神经和精神疾病，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层流命运的机制（包括分子表达）。Hevner博士是一名研究皮层发育的神经病理学家/神经科学家。他近期的职业目标是：1)建立一个强有力的独立研究项目；2)通过与一位更资深的专家（大卫·普莱斯博士）合作，扩大他实验室的技术范围；3)通过加强与华盛顿大学同事的互动，提高工作效率；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华盛顿大学主校区附近的Harborview医学中心（HMC）的一个现代化的，设备齐全的研究设施中。HMC和华盛顿大学支持一个由有成就的发育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，皮层的每一层都含有投射神经元，这些神经元与细胞大小、轴突连接和分子表达的相似性有关。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，一些特性可能在有丝分裂后受到调节。这一提议验证了层特异性分子表达可以在有丝分裂后调节的假设。新产生的有丝分裂后神经元将被移植到对照组（同龄）胚胎、异龄（不同年龄）胚胎或Rein突变胚胎的皮层中，这些胚胎缺乏Reelin并且皮层组织紊乱。移植细胞的分子表达将使用一组层特异性标记进行检查。如果分子命运在异慢性或Rein突变的皮层中被改变，这将表明层状命运的某些方面可以在有丝分裂后被调节。

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.