Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA, USA.
Cell. 2019 Feb 7;176(4):743-756.e17. doi: 10.1016/j.cell.2019.01.017.
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.
直接比较人类和非人类灵长类动物的大脑可以揭示人类大脑显著特化的分子途径。然而，在大脑大小差异首次出现的新皮质神经发生期间，无法获得黑猩猩组织。为了确定皮质发育的人类特异性特征，我们利用了最近的创新技术，这些技术允许从黑猩猩中生成多能干细胞衍生的类器官。尽管存在代谢差异，但类器官模型保留了与主要细胞类型和发育过程相关的基因调控网络。我们进一步鉴定了 261 个在人类中与黑猩猩类器官和猕猴皮质相比差异表达的基因，这些基因在最近的基因重复中富集，包括多个 PI3K-AKT-mTOR 信号通路的调节剂。我们观察到人类放射状胶质细胞中该途径的激活增加，这取决于在人类中特异性上调的两个受体：INSR 和 ITGB8。我们的研究结果为系统分析导致人类大脑发育和进化的分子变化奠定了基础。
