The role of retinoic acid signaling in patterning the human cerebral cortex

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ABSTRACT/PROJECT SUMMARY This application presents a five-year mentored research and training plan that will prepare Dr. Cathryn Cadwell to be a leader in the field of cortical development and circuit assembly. Dr. Cadwell completed her MD and PhD in Neuroscience at Baylor College of Medicine, where she studied the role of cell type and cell lineage in shaping cortical circuits in the lab of Dr. Andreas Tolias, and is now completing her clinical fellowship in Neuropathology at the University of California, San Francisco. Dr. Cadwell’s long-term career goal is to advance our understanding of the pathological processes underlying neurodevelopmental and neuropsychiatric disorders. This project will facilitate foundational discoveries for her independent research program, as she seeks to delineate the mechanisms and functional consequences of cortical areal specification. Different areas of the human brain give rise to unique cognitive abilities. For example, expansion of the lateral prefrontal cortex (PFC) in humans is thought to underlie higher-order cognitive processes such as decision-making, planning and working memory. Recent data has implicated retinoic acid (RA), a derivative of vitamin A, as a key player in the early development of the PFC in humans; however, the precise mechanism by which RA specifies PFC identities is unknown. This proposal leverages a human induced pluripotent stem cell– derived cerebral organoid model, which recapitulates many aspects of early human brain development, to test the hypothesis that RA acts in a cell type–specific manner to specify PFC identities. Using this model, Dr. Cadwell proposes to 1) identify the nuclear receptors and gene regulatory elements that mediate RA signaling in human cortical progenitors and 2) determine whether PFC-like areal fate is stable after RA induction. This work will generate fundamental knowledge about the role of RA in patterning the cerebral cortex, and may provide insights into neurodevelopmental disorders associated abnormal cortical areal specification. The proposed career development plan includes training in cerebral organoid models, epigenetic techniques and analysis of large-scale data sets. Dr. Cadwell will learn all of the skills needed for an independent research career, including supervising trainees and staff, grant writing, and scientific communication. She has assembled a world-class mentorship team with complementary expertise in organoids and human brain development (Primary mentor, Dr. Tomasz Nowakowski), molecular mechanisms of cortical development and patterning (Co-mentor Dr. John Rubenstein and Advisory Committee Member Dr. Sam Pleasure), gene regulation (Advisory Committee Member Dr. Nadav Ahituv), analysis of large-scale genomic data (Dr. Katie Pollard), and neuropathology of neurodevelopmental disorders (Dr. Eric Huang). Dr. Cadwell, her mentors, and the Department of Pathology at UCSF are fully committed to this proposal and to her goal of becoming an independent physician-neuroscientist by the completion of this training period.