LISBON, JUNE 13, 2019

Arnold Kriegstein - USA
University of California 

Genomic Insights into Human-Specific Brain Development, Evolution, and Disease

Department of Neurology
John G. Bowes Distinguished Professor in Stem Cell and Tissue Biology
Director, The Eli and Edythe Broad Center of Regeneration Medicine and
Stem Cell Research, UCSF
UCSF School of Medicine

The human cerebral cortex has the largest number of neurons among living mammals. The features of cortical development that underlie the evolutionary expansion of the human cortex as well as susceptibility to disease are largely
unexplored. These features cannot be studied in animal models and require the use of primary human tissue samples or in vitro human models such as stem cell-derived organoids. We have identified outer radial glia (oRG) as a neural stem cell population that generate a significant number of human cortical neurons, and have sequenced mRNA from single human progenitor cells and young neurons for unbiased classification of cell identity and for detection of activated signaling pathways. oRG cells are enriched in genes related to extracellular matrix production, epithelial-mesenchymal transition, and stem cell maintenance, suggesting mechanisms by which human oRG cells actively maintain their neural stem cell niche. Additionally, our genomic data has informed a novel model of primate corticogenesis, suggested a relationship between oRG cells and brain tumors, and provided insights into the specific cell types affected by genetic forms of lissencephaly. Our census of cell types and lineages along with their molecular and physiological properties also supports comparisons of the same cell subtypes generated from luripotent stem cells in in vitro models of development. To identify human-specific features of cortical development and disease, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from human and non-human primates. We evaluated the fidelity of organoid models to primary human and macaque cortex, finding organoid models preserve gene regulatory networks related to cell types and developmental processes but exhibit increased metabolic stress. Our molecular insights also show that human oRG cells are dependent upon mTOR signaling, and are thus likely to be targeted by disease causing mutations of this signaling pathway, as implicated in autism.

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