2. Academic Validation
  3. OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome

OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome

  • Cell Stem Cell. 2019 Jun 6;24(6):908-926.e8. doi: 10.1016/j.stem.2019.04.014.
Ranjie Xu 1,  Andrew T Brawner 2,  Shenglan Li 3,  Jing-Jing Liu 4,  Hyosung Kim 5,  Haipeng Xue 3,  Zhiping P Pang 4,  Woo-Yang Kim 6,  Ronald P Hart 5,  Ying Liu 3,  Peng Jiang 7
Affiliations

Affiliations

  • 1 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Developmental Neuroscience, Munroe-Meyer Institute and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 2 Department of Developmental Neuroscience, Munroe-Meyer Institute and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 3 Department of Neurosurgery and Center for Stem Cell and Regenerative Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  • 4 Department of Neuroscience and Cell Biology and Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
  • 5 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
  • 6 Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
  • 7 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Developmental Neuroscience, Munroe-Meyer Institute and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: peng.jiang@rutgers.edu.
PMID: 31130512 DOI: 10.1016/j.stem.2019.04.014
Abstract

Down syndrome (DS) is a common neurodevelopmental disorder, and cognitive defects in DS patients may arise from imbalances in excitatory and inhibitory neurotransmission. Understanding the mechanisms underlying such imbalances may provide opportunities for therapeutic intervention. Here, we show that human induced pluripotent stem cells (hiPSCs) derived from DS patients overproduce OLIG2+ ventral forebrain neural progenitors. As a result, DS hiPSC-derived cerebral organoids excessively produce specific subclasses of GABAergic interneurons and cause impaired recognition memory in neuronal chimeric mice. Increased OLIG2 expression in DS cells directly upregulates interneuron lineage-determining transcription factors. shRNA-mediated knockdown of OLIG2 largely reverses abnormal gene expression in early-stage DS neural progenitors, reduces interneuron production in DS organoids and chimeric mouse brains, and improves behavioral deficits in DS chimeric mice. Thus, altered OLIG2 expression may underlie neurodevelopmental abnormalities and cognitive defects in DS patients.

Keywords

Down syndrome; OLIG1; OLIG2; brain organoid; chimeric mouse brain; human induced pluripotent stem cell; interneuron; neurodevelopmental disorder.

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