Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder

Job O. Jong, Ceyda Llapashtica, Matthieu Genestine, Kevin Strauss, Frank Provenzano, Yan Sun, Huixiang Zhu, Giuseppe P. Cortese, Francesco Brundu, Karlla W. Brigatti, Barbara Corneo, Bianca Migliori, Raju Tomer, Steven A. Kushner, Christoph Kellendonk, Jonathan A. Javitch, Bin Xu () and Sander Markx ()
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Job O. Jong: Columbia University
Ceyda Llapashtica: Columbia University
Matthieu Genestine: Columbia University
Kevin Strauss: Clinic for Special Children
Frank Provenzano: Columbia University
Yan Sun: Columbia University
Huixiang Zhu: Columbia University
Giuseppe P. Cortese: Columbia University
Francesco Brundu: Columbia University
Karlla W. Brigatti: Clinic for Special Children
Barbara Corneo: Columbia University
Bianca Migliori: Tech4Health and Neuroscience Institutes, NYU Langone Health
Raju Tomer: Columbia University
Steven A. Kushner: Columbia University
Christoph Kellendonk: Columbia University
Jonathan A. Javitch: Columbia University
Bin Xu: Columbia University
Sander Markx: Columbia University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.

Date: 2021
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DOI: 10.1038/s41467-021-24358-4

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