Cell Type-specific Alternative Splicing Controls Cerebral Cortical Development

 描述（由申请人提供）：人类基因组包含的基因比许多看似简单的生物体少，但人类-特别是人类大脑-通过选择性前mRNA剪接创造了显着的蛋白质多样性。在自闭症患者的大脑中反复发现了选择性剪接网络的失调，这表明选择性剪接在人类心理健康中起着关键作用。然而，目前还不清楚人类大脑在发育过程中何时以及如何获得复杂的选择性剪接，我们目前的知识缺乏对选择性剪接的调节如何与发育性人类大脑疾病相关的系统性理解。一个主要的差距是缺乏一个直接比较的差异剪接外显子之间的早期人类神经祖细胞和分化的神经元的发展。在这个项目中，张博士将结合联合收割机荧光激活细胞分选，RNA测序和多学科功能方法来测试细胞类型特异性选择性剪接对大脑皮层发育执行重要控制层的假设。具体而言，该提议旨在：1]鉴定小鼠和人类中皮质神经祖细胞和神经元之间的全基因组可变剪接外显子，2]研究可变剪接外显子的功能影响，以及3]鉴定引起异常可变剪接和发育人脑障碍的突变。张晓昌博士是波士顿儿童医院（BCH）和哈佛医学院的讲师，他提出的4年辅导职业计划将在Christopher A.沃尔什在遗传学和基因组学部在BCH。Zhang博士的背景是分子和发育生物学，他的长期职业目标是成为一名独立的研究者，在选择性剪接介导的大脑皮层发育调控和人类大脑疾病方面具有专业知识。在人类大脑皮层发育和疾病领域的世界领先专家沃尔什博士的指导下，张博士开发了一个研究和培训平台，使他能够获得必要的实验技能和知识，以便在指导和独立的环境中取得成效。为了实现这一目标，张博士将利用沃尔什实验室在人类遗传学和发育神经生物学方面的专业知识和资源，获得相关研究领域的额外技能和培训，并与专家团队建立合作关系。鉴于BCH的杰出记录，该计划最好在BCH的沃尔什实验室进行 在丰富的协作环境中培养研究科学家。

 DESCRIPTION (provided by applicant): The human genome contains fewer genes than many seemingly simpler organisms, but humans-especially the human brains-create remarkable protein diversity by alternative pre-mRNA splicing. Dysregulations of alternative splicing networks have been repeatedly found in autistic brains, indicating critical roles of alternative splicing in human mental health. However, it's unclear when and how the human brain acquires complex alternative splicing during development, and our current knowledge lacks a systematic understanding of how the regulation of alternative splicing relates to developmental human brain disorders. A major gap is the lack of a direct comparison of differentially spliced exons between early human neural progenitors and differentiated neurons in development. In this project, Dr. Zhang will combine fluorescence activated cell sorting, RNA sequencing and multidisciplinary functional approaches to test the hypothesis that cell type-specific alternative splicing executes an important layer of control on cerebral cortical development. Specifically, this proposal aims to: 1] Identify genome-wide alternatively spliced exons between cortical neural progenitors and neurons in mice and humans, 2] Investigate the functional impact of alternatively spliced exons, and 3] Identify mutations that cause aberrant alternative splicing and developmental human brain disorders. Dr. Xiaochang Zhang is an Instructor at the Boston Children's Hospital (BCH) and Harvard Medical School, and his proposed 4-year mentored career plan will be performed in the laboratory of Dr. Christopher A. Walsh in the Division of Genetics and Genomics at BCH. Dr. Zhang's background is in molecular and developmental biology, and his long-term career goal is to become an independent investigator with expertise in alternative splicing mediated regulation of cerebral cortex development and human brain disorders. Under the mentorship of Dr. Walsh, a world leading expert in the fields of human cerebral cortical development and disorders, Dr. Zhang has developed a research and training platform that will allow him to acquire the experimental skills and knowledge necessary to be productive in both a mentored and independent setting. To accomplish this, Dr. Zhang will take advantage of the expertise and resources in human genetics and developmental neurobiology of the Walsh lab, acquire additional skills and training in relevant research areas, and establish collaboration with a team of experts. The plan is ideally carried out in the Walsh lab at BCH, given its distinguished record for training research scientists in a rich and collaborative environment.