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Autism genes converge on asynchronous development of shared neuron classes

Author

Listed:
  • Bruna Paulsen

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Silvia Velasco

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    The Royal Children’s Hospital)

  • Amanda J. Kedaigle

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Martina Pigoni

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Giorgia Quadrato

    (Harvard University
    University of Southern California)

  • Anthony J. Deo

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Boston Children’s Hospital, Harvard Medical School
    Rutgers-Robert Wood Johnson Medical School)

  • Xian Adiconis

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Ana Uzquiano

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Rafaela Sartore

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Sung Min Yang

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Sean K. Simmons

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Panagiotis Symvoulidis

    (Massachusetts Institute of Technology (MIT))

  • Kwanho Kim

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Kalliopi Tsafou

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Archana Podury

    (Massachusetts Institute of Technology (MIT)
    Harvard Medical School)

  • Catherine Abbate

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Ashley Tucewicz

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Samantha N. Smith

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Alexandre Albanese

    (Massachusetts Institute of Technology (MIT))

  • Lindy Barrett

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Neville E. Sanjana

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    New York Genome Center
    New York University)

  • Xi Shi

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Kwanghun Chung

    (Massachusetts Institute of Technology (MIT)
    Massachusetts Institute of Technology (MIT)
    New York Genome Center)

  • Kasper Lage

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Edward S. Boyden

    (Massachusetts Institute of Technology (MIT)
    Harvard Medical School
    Massachusetts Institute of Technology (MIT)
    Massachusetts Institute of Technology (MIT))

  • Aviv Regev

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology (MIT)
    South San Francisco)

  • Joshua Z. Levin

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Paola Arlotta

    (Harvard University
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

Abstract

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1–6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes—SUV420H1 (also known as KMT5B), ARID1B and CHD8—in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages—γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons—but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

Suggested Citation

  • Bruna Paulsen & Silvia Velasco & Amanda J. Kedaigle & Martina Pigoni & Giorgia Quadrato & Anthony J. Deo & Xian Adiconis & Ana Uzquiano & Rafaela Sartore & Sung Min Yang & Sean K. Simmons & Panagiotis, 2022. "Autism genes converge on asynchronous development of shared neuron classes," Nature, Nature, vol. 602(7896), pages 268-273, February.
  • Handle: RePEc:nat:nature:v:602:y:2022:i:7896:d:10.1038_s41586-021-04358-6
    DOI: 10.1038/s41586-021-04358-6
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    Citations

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    Cited by:

    1. Congyi Lu & Görkem Garipler & Chao Dai & Timothy Roush & Jose Salome-Correa & Alex Martin & Noa Liscovitch-Brauer & Esteban O. Mazzoni & Neville E. Sanjana, 2023. "Essential transcription factors for induced neuron differentiation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Jie Zhang & Gongcheng Hu & Yuli Lu & Huawei Ren & Yin Huang & Yulin Wen & Binrui Ji & Diyang Wang & Haidong Wang & Huisheng Liu & Ning Ma & Lingling Zhang & Guangjin Pan & Yibo Qu & Hua Wang & Wei Zha, 2024. "CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Wang, Xueyan & Tian, Hua & Shu, Gequn & Yang, Zhao, 2024. "Study on flammability limit and combustion reactions behaviors of R744/R152a environmentally friendly mixed working fluid by experiments and molecular dynamic simulation," Energy, Elsevier, vol. 304(C).
    4. Carolina Gracia-Diaz & Yijing Zhou & Qian Yang & Reza Maroofian & Paula Espana-Bonilla & Chul-Hwan Lee & Shuo Zhang & Natàlia Padilla & Raquel Fueyo & Elisa A. Waxman & Sunyimeng Lei & Garrett Otrimsk, 2023. "Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Rebecca Sebastian & Kang Jin & Narciso Pavon & Ruby Bansal & Andrew Potter & Yoonjae Song & Juliana Babu & Rafael Gabriel & Yubing Sun & Bruce Aronow & ChangHui Pak, 2023. "Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Mattia Zaghi & Federica Banfi & Luca Massimino & Monica Volpin & Edoardo Bellini & Simone Brusco & Ivan Merelli & Cristiana Barone & Michela Bruni & Linda Bossini & Luigi Antonio Lamparelli & Laura Pi, 2023. "Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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