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.

Public Health Relevance

Alternative splicing creates remarkable protein diversity in humans, and the aberrant regulation of alternative splicing has been repeatedly found in autistic brains, indicating the critical impact of alternative splicing on human mental health. However, it remains unexplored whether or how alternative splicing regulates neural stem cell proliferation and differentiation during human brain development. This project will create a genome- wide map of alternatively spliced exons between neural progenitors and neurons in developing mouse and human brains, and relate these alternative exons to pathogenic mutations that cause pediatric human brain disorders including but not limited to epilepsy and microcephaly (abnormally small brain).

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research & Training (K01)
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Developmental Brain Disorders Study Section (DBD)
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Driscoll, Jamie
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Boston Children's Hospital
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United States
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Zhang, Xiaochang; Chen, Ming Hui; Wu, Xuebing et al. (2016) Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex. Cell 166:1147-1162.e15