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Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex

Oliver L. Eichmüller, Nina S. Corsini, Ábel Vértesy, Theresa Scholl, Victoria-Elisabeth Gruber, Angela M. Peer, Julia Chu, Maria Novatchkova, Mercedes F. Paredes, Martha Feucht, Jürgen A. Knoblich
doi: https://doi.org/10.1101/2020.02.27.967802
Oliver L. Eichmüller
1IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna Biocenter (VBC), Vienna, Austria
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Nina S. Corsini
1IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna Biocenter (VBC), Vienna, Austria
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  • For correspondence: nina.corsini@imba.oeaw.ac.at juergen.knoblich@imba.oeaw.ac.at
Ábel Vértesy
1IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna Biocenter (VBC), Vienna, Austria
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Theresa Scholl
2Medical University of Vienna, Department of Pediatric and Adolescent Medicine, Vienna, Austria
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Victoria-Elisabeth Gruber
2Medical University of Vienna, Department of Pediatric and Adolescent Medicine, Vienna, Austria
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Angela M. Peer
1IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna Biocenter (VBC), Vienna, Austria
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Julia Chu
3Department of Neurology, University of California, San Francisco, USA
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Maria Novatchkova
1IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna Biocenter (VBC), Vienna, Austria
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Mercedes F. Paredes
3Department of Neurology, University of California, San Francisco, USA
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Martha Feucht
2Medical University of Vienna, Department of Pediatric and Adolescent Medicine, Vienna, Austria
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Jürgen A. Knoblich
1IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna Biocenter (VBC), Vienna, Austria
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  • For correspondence: nina.corsini@imba.oeaw.ac.at juergen.knoblich@imba.oeaw.ac.at
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Summary

Although the intricate and prolonged development of the human brain critically distinguishes it from other mammals1, our current understanding of neurodevelopmental diseases is largely based on work using animal models. Recent studies revealed that neural progenitors in the human brain are profoundly different from those found in rodent animal models2–5. Moreover, post-mortem studies revealed extensive migration of interneurons into the late-gestational and post-natal human prefrontal cortex that does not occur in rodents6. Here, we use cerebral organoids to show that overproduction of mid-gestational human interneurons causes Tuberous Sclerosis Complex (TSC), a severe neuro-developmental disorder associated with mutations in TSC1 and TSC2. We identify a previously uncharacterized population of caudal late interneuron progenitors, the CLIP-cells. In organoids derived from patients carrying heterozygous TSC2 mutations, dysregulation of mTOR signaling leads to CLIP-cell over-proliferation and formation of cortical tubers and subependymal tumors. Surprisingly, second-hit events resulting from copy-neutral loss-of-heterozygosity (cnLOH) are not causative for but occur during the progression of tumor lesions. Instead, EGFR signaling is required for tumor proliferation, opening up a promising approach to treat TSC lesions. Our study demonstrates that the analysis of developmental disorders in organoid models can lead to fundamental insights into human brain development and neuropsychiatric disorders.

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Posted February 27, 2020.
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Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex
Oliver L. Eichmüller, Nina S. Corsini, Ábel Vértesy, Theresa Scholl, Victoria-Elisabeth Gruber, Angela M. Peer, Julia Chu, Maria Novatchkova, Mercedes F. Paredes, Martha Feucht, Jürgen A. Knoblich
bioRxiv 2020.02.27.967802; doi: https://doi.org/10.1101/2020.02.27.967802
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Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex
Oliver L. Eichmüller, Nina S. Corsini, Ábel Vértesy, Theresa Scholl, Victoria-Elisabeth Gruber, Angela M. Peer, Julia Chu, Maria Novatchkova, Mercedes F. Paredes, Martha Feucht, Jürgen A. Knoblich
bioRxiv 2020.02.27.967802; doi: https://doi.org/10.1101/2020.02.27.967802

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