Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution. Pollen, A. A, Bhaduri, A., Andrews, M. G, Nowakowski, T. J, Meyerson, O. S, Mostajo-Radji, M. A, Di Lullo, E., Alvarado, B., Bedolli, M., Dougherty, M. L, Fiddes, I. T, Kronenberg, Z. N, Shuga, J., Leyrat, A. A, West, J. A, Bershteyn, M., Lowe, C. B, Pavlovic, B. J, Salama, S. R, Haussler, D., Eichler, E. E, & Kriegstein, A. R Cell, 176(4):743–756.e17, February, 2019.
abstract   bibtex   
Direct comparisons of human and non-human primate brains can reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. Despite metabolic differences, organoid models preserve gene regulatory networks related to primary cell types and developmental processes. We further identified 261 differentially expressed genes in human compared to both chimpanzee organoids and macaque cortex, enriched for recent gene duplications, and including multiple regulators of PI3K-AKT-mTOR signaling. We observed increased activation of this pathway in human radial glia, dependent on two receptors upregulated specifically in human: INSR and ITGB8. Our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.
@ARTICLE{Pollen2019-vm,
  title    = "Establishing Cerebral Organoids as Models of {Human-Specific}
              Brain Evolution",
  author   = "Pollen, Alex A and Bhaduri, Aparna and Andrews, Madeline G and
              Nowakowski, Tomasz J and Meyerson, Olivia S and Mostajo-Radji,
              Mohammed A and Di Lullo, Elizabeth and Alvarado, Beatriz and
              Bedolli, Melanie and Dougherty, Max L and Fiddes, Ian T and
              Kronenberg, Zev N and Shuga, Joe and Leyrat, Anne A and West, Jay
              A and Bershteyn, Marina and Lowe, Craig B and Pavlovic, Bryan J
              and Salama, Sofie R and Haussler, David and Eichler, Evan E and
              Kriegstein, Arnold R",
  abstract = "Direct comparisons of human and non-human primate brains can
              reveal molecular pathways underlying remarkable specializations
              of the human brain. However, chimpanzee tissue is inaccessible
              during neocortical neurogenesis when differences in brain size
              first appear. To identify human-specific features of cortical
              development, we leveraged recent innovations that permit
              generating pluripotent stem cell-derived cerebral organoids from
              chimpanzee. Despite metabolic differences, organoid models
              preserve gene regulatory networks related to primary cell types
              and developmental processes. We further identified 261
              differentially expressed genes in human compared to both
              chimpanzee organoids and macaque cortex, enriched for recent gene
              duplications, and including multiple regulators of PI3K-AKT-mTOR
              signaling. We observed increased activation of this pathway in
              human radial glia, dependent on two receptors upregulated
              specifically in human: INSR and ITGB8. Our findings establish a
              platform for systematic analysis of molecular changes
              contributing to human brain development and evolution.",
  journal  = "Cell",
  volume   =  176,
  number   =  4,
  pages    = "743--756.e17",
  month    =  feb,
  year     =  2019,
  keywords = "cerebral organoids; chimpanzee; cortical development;
              human-specific evolution; mTOR; macaque; neural progenitor cells;
              radial glia; single-cell RNA sequencing",
  language = "en"
}

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