期刊
NATURE
卷 592, 期 7854, 页码 421-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03343-3
关键词
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资金
- Stanford Bio-X Interdisciplinary Initiatives Seed Grant
- NIH [T32 GM007790, 2R01GM097171-05A1]
- Department of Defense National Defense Science and Engineering Graduate Fellowship
- Stanford Center for Computational, Evolutionary and Human Genomics
- Stanford Medicine's Dean's Fellowship
- Stanford Medicine Maternal & Child Health Research Institute Postdoctoral Support Program
- American Epilepsy Society Postdoctoral Research Fellowship
- Stanford Wu Tsai Neurosciences Institute's Big Idea Grants on Brain Rejuvenation and Human Brain Organogenesis
- Kwan Research Fund
- New York Stem Cell Foundation-Robertson Investigator Award
- Chan Zuckerberg Ben Barres Investigator Award
- National Institutes of Health, Office of Research Infrastructure Programs/OD [P51OD011132]
A new platform for studying species divergence in cerebral cortical development was developed by fusing human and chimpanzee induced pluripotent stem cells to create a panel of tetraploid hybrid stem cells. This approach revealed specific gene expression divergence and potential for neural behavioral abnormalities related to human evolution.
Among primates, humans display a unique trajectory of development that is responsible for the many traits specific to our species. However, the inaccessibility of primary human and chimpanzee tissues has limited our ability to study human evolution. Comparative in vitro approaches using primate-derived induced pluripotent stem cells have begun to reveal species differences on the cellular and molecular levels(1,2). In particular, brain organoids have emerged as a promising platform to study primate neural development in vitro(3-5), although cross-species comparisons of organoids are complicated by differences in developmental timing and variability of differentiation(6,7). Here we develop a new platform to address these limitations by fusing human and chimpanzee induced pluripotent stem cells to generate a panel of tetraploid hybrid stem cells. We applied this approach to study species divergence in cerebral cortical development by differentiating these cells into neural organoids. We found that hybrid organoids provide a controlled system for disentangling cis- and trans-acting gene-expression divergence across cell types and developmental stages, revealing a signature of selection on astrocyte-related genes. In addition, we identified an upregulation of the human somatostatin receptor 2 gene (SSTR2), which regulates neuronal calcium signalling and is associated with neuropsychiatric disorders(8,9). We reveal a human-specific response to modulation of SSTR2 function in cortical neurons, underscoring the potential of this platform for elucidating the molecular basis of human evolution.
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