Cell Type-specific Alternative Splicing Controls Cerebral Cortical Development

 描述(申请人提供)：人类基因组包含的基因比许多看似更简单的有机体要少，但人类--尤其是人脑--通过替代的前信使核糖核酸剪接创造了非凡的蛋白质多样性。在自闭症患者的大脑中反复发现选择性剪接网络的调控异常，这表明选择性剪接在人类心理健康中扮演着关键角色。然而，目前尚不清楚人脑在发育过程中何时以及如何获得复杂的选择性剪接，而且我们目前的知识缺乏系统地了解选择性剪接的调节与人类大脑发育障碍的关系。一个主要的差距是缺乏对早期人类神经前体细胞和发育中分化的神经元之间差异剪接外显子的直接比较。在这个项目中，张博士将结合荧光激活的细胞分选、RNA测序和多学科功能方法来检验这样一个假设，即特定细胞类型的选择性剪接对大脑皮层发育起着重要的控制层作用。具体地说，这项建议旨在：1)确定小鼠和人类皮质神经前体细胞和神经元之间的全基因组选择性剪接外显子；2)研究选择性剪接外显子的功能影响；3)识别导致异常选择性剪接和人类大脑发育障碍的突变。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年指导职业计划将在波士顿儿童医院遗传学和基因组学部Christopher A.Walsh博士的实验室进行。张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员，在大脑皮质发育和人脑疾病的选择性剪接调节方面拥有专业知识。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，使他能够获得在指导和独立环境下进行生产所需的实验技能和知识。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。鉴于其卓越的记录，该计划理想地在BCH的沃尔什实验室进行 用于在丰富和协作的环境中培训研究科学家。

 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.