A major long-term goal of this proposal is to understand human brain development and the origins of neurodevelopmental diseases. The cerebral cortex is a structure where model systems, such as mouse or rat, may not capture the complexity of architecture and function relevant for understanding human development and disease. This proposal aims to address the gap in our understanding of human cortical development through the study of primary tissue complemented by human stem cell-derived in vitro model systems, using ?cerebral organoids?. Understanding human-specific aspects of brain development is not only critically important for understanding the etiology of neurodevelopmental disorders, including autism and schizophrenia and ultimately developing therapies, but will also benefit our understanding of human cortical evolution, the diversity and lineage of neural cell types, and the mechanisms of cortical expansion - it will help define what makes us unique. The developing human brain contains an enlarged proliferative region, the outer subventricular zone (OSVZ) that is not present in rodents. This study will target two recently discovered neural progenitor cell types found in the OSVZ, outer radial glia (oRG) and intermediate progenitor (IP) cells. These cell types are particularly important as they underlie the huge developmental and evolutionary expansion of the human brain. This proposal seeks to illuminate the complexity of human cortical development in terms of the genomic, cellular, and behavioral features of its constituent oRG and IP neural progenitor cells and their progeny through the key stages of neurogenesis. We plan to discover lineage trajectories that define progenitor-progeny relationships and determine the cellular fates of clonal descendants. We will use novel oRG and IPC markers to enrich progenitor cell populations for analysis, explore the intracellular signaling networks that regulate IP cell expansion, investigate the role of distinct neurogenic niches in creating neuronal diversity, and examine neuron to progenitor signaling pathways that may regulate IPC neurogenesis. Additionally, we will explore the role of oRGs and IPCs in lissencephaly and related neurodevelopmental diseases, and pursue an intriguing relationship between oRG cells and invasive glioblastoma. These ambitious goals are attainable due to recent technological advances, including improvements in single cell genomics, bioinformatics, real time imaging of primary tissue samples, and in vitro models of human cortical development. The outcome holds promise to transform our understanding of human brain development in health and disease.

Public Health Relevance

This proposal seeks to discover how the neural stem and progenitor cells of the developing brain produce the large diversity of nerve cell types found in the human cerebral cortex. Developing therapeutic approaches to disorders of brain development ranging from major malformations to diseases such as autism and schizophrenia will require an understanding of the human-specific features of cortical development that are the subject of this study.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS097305-02
Application #
9391713
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Lavaute, Timothy M
Project Start
2016-12-01
Project End
2024-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Bershteyn, Marina; Nowakowski, Tomasz J; Pollen, Alex A et al. (2017) Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia. Cell Stem Cell 20:435-449.e4
Subramanian, Lakshmi; Bershteyn, Marina; Paredes, Mercedes F et al. (2017) Dynamic behaviour of human neuroepithelial cells in the developing forebrain. Nat Commun 8:14167
Nowakowski, Tomasz J; Bhaduri, Aparna; Pollen, Alex A et al. (2017) Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex. Science 358:1318-1323
Di Lullo, Elizabeth; Kriegstein, Arnold R (2017) The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci 18:573-584
Müller, Sören; Liu, Siyuan John; Di Lullo, Elizabeth et al. (2016) Single-cell sequencing maps gene expression to mutational phylogenies in PDGF- and EGF-driven gliomas. Mol Syst Biol 12:889
Nowakowski, Tomasz J; Pollen, Alex A; Sandoval-Espinosa, Carmen et al. (2016) Transformation of the Radial Glia Scaffold Demarcates Two Stages of Human Cerebral Cortex Development. Neuron 91:1219-1227
Retallack, Hanna; Di Lullo, Elizabeth; Arias, Carolina et al. (2016) Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci U S A 113:14408-14413