22 mars 2018: prof. Arnold Kriegstein
Jeudi 22 mars 2018
12h30, CMU - Auditoire Alex-F. Müller (A250)
Arnold KRIEGSTEIN, MD PhD
Professor of Neurology
Director, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF
«A new understanding of human brain development in health and disease»
Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone radial glia (oRG) appear to generate the majority of human cortical neurons, their molecular features remain elusive. An evolutionary increase in the number of oRG cells and their transit amplifying daughter cells likely contributed to increased cortical size and complexity in the human brain. We have begun to sequence mRNA from single human progenitor cells and young neurons for unbiased classification of cell identity and for detection of activated signaling pathways. We observed a functional coherence among genes enriched in oRG cells that relate to extracellular matrix production, epithelial-to-mesenchymal transition, and stem cell maintenance, suggesting mechanisms by which human oRG cells actively maintain the outer subventricular zone as a neural stem cell niche. Using single cell clonal lineage analysis, we find that oRG cells can generate hundreds of daughter neurons of deep and upper layer identity, establishing the extensive proliferative and neurogenic capacity of this cell type. Our single cell data has also revealed novel gene differences between cells of the same subtype that relate to areal position. Finally, by using novel markers that reveal the morphology of oRG or ventricular radial glia cells selectively, we find that oRG cells form the primary scaffold for migration of neurons to the cortical plate during mid- and late-phases of cortical neurogenesis. More generally, we have expanded this approach to identify the genes and pathways distinguishing diverse cell types during cortical development.
These molecular insights show that among human neural stem and progenitor cells, only oRG cells are dependent upon mTOR signaling, and are thus likely to be targeted by disease causing mutations of this signaling pathway, as for example, in autism. Additionally, our genomic data has informed a novel model of primate corticogenesis, suggested a relationship between oRG cells and brain tumors, provided insights into the specific cell types affected by genetic forms of lissencephaly, and have helped identify the mechanism of Zika virus microcephaly.
Biography
Dr. Kriegstein received a BS from Yale University (1971), and MD and PhD from New York University (1977). He completed Neurology Residency at the Brigham and Women’s, Children’s, and Beth Israel Hospitals, Boston, and is a board-certified clinical neurologist. He has held academic appointments at Stanford, Yale, and Columbia before joining UCSF in 2004. In 2001 he was named the John and Elizabeth Harris Professor of Neurology and became the founding Director of the Neural Stem Cell Program at Columbia University. Dr. Kriegstein is currently the John Bowes Distinguished Professor in Stem Cell and Tissue Biology and Founding Director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. He was elected a member of the National Academy of Medicine in 2008. Dr. Kriegstein’s research focuses on the stem cell niche and ways neural stem and progenitor cells produce neurons in the developing brain. He is particularly interested in human cortical development, brain evolution, and neurodevelopmental disease.