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Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes

Author

Listed:
  • Yueqi Wang

    (University of Utah
    University of Utah)

  • Simone Chiola

    (University of Utah)

  • Guang Yang

    (University of Utah
    University of Utah)

  • Chad Russell

    (University of Utah)

  • Celeste J. Armstrong

    (University of Utah)

  • Yuanyuan Wu

    (University of Utah)

  • Jay Spampanato

    (University of Utah)

  • Paisley Tarboton

    (University of Utah)

  • H. M. Arif Ullah

    (University of Utah)

  • Nicolas U. Edgar

    (University of Utah)

  • Amelia N. Chang

    (Harvard Medical School)

  • David A. Harmin

    (Harvard Medical School)

  • Vittoria Dickinson Bocchi

    (University of Milan
    Istituto Nazionale di Genetica Molecolare)

  • Elena Vezzoli

    (University of Milan
    Istituto Nazionale di Genetica Molecolare)

  • Dario Besusso

    (University of Milan
    Istituto Nazionale di Genetica Molecolare)

  • Jun Cui

    (Montana State University)

  • Elena Cattaneo

    (University of Milan
    Istituto Nazionale di Genetica Molecolare)

  • Jan Kubanek

    (University of Utah)

  • Aleksandr Shcheglovitov

    (University of Utah
    University of Utah
    University of Utah)

Abstract

Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial neural progenitors, excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and exhibit predictable organization and cytoarchitecture. We comprehensively characterize the properties of neurons in SNR-derived organoids and identify transcriptional programs associated with the specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development. We also demonstrate that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability-associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits and impaired expression of several clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable model for studying human telencephalic cortico-striatal development and identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity.

Suggested Citation

  • Yueqi Wang & Simone Chiola & Guang Yang & Chad Russell & Celeste J. Armstrong & Yuanyuan Wu & Jay Spampanato & Paisley Tarboton & H. M. Arif Ullah & Nicolas U. Edgar & Amelia N. Chang & David A. Harmi, 2022. "Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33364-z
    DOI: 10.1038/s41467-022-33364-z
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    2. Maura Galimberti & Maria R. Nucera & Vittoria D. Bocchi & Paola Conforti & Elena Vezzoli & Matteo Cereda & Camilla Maffezzini & Raffaele Iennaco & Andrea Scolz & Andrea Falqui & Chiara Cordiglieri & M, 2024. "Huntington’s disease cellular phenotypes are rescued non-cell autonomously by healthy cells in mosaic telencephalic organoids," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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