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Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content

Author

Listed:
  • Fabio Papes

    (University of Campinas
    University of California San Diego
    University of Campinas)

  • Antonio P. Camargo

    (University of Campinas
    University of Campinas
    Lawrence Berkeley National Laboratory)

  • Janaina S. Souza

    (University of California San Diego)

  • Vinicius M. A. Carvalho

    (University of Campinas
    University of California San Diego
    University of Campinas)

  • Ryan A. Szeto

    (University of California San Diego)

  • Erin LaMontagne

    (University of California San Diego)

  • José R. Teixeira

    (University of Campinas
    University of Campinas)

  • Simoni H. Avansini

    (University of California San Diego
    University of Campinas)

  • Sandra M. Sánchez-Sánchez

    (University of California San Diego)

  • Thiago S. Nakahara

    (University of Campinas
    University of Campinas)

  • Carolina N. Santo

    (University of Campinas
    University of Campinas
    University of Campinas)

  • Wei Wu

    (University of California San Diego)

  • Hang Yao

    (University of California San Diego)

  • Barbara M. P. Araújo

    (University of Campinas)

  • Paulo E. N. F. Velho

    (University of Campinas)

  • Gabriel G. Haddad

    (University of California San Diego
    University of California San Diego
    Rady Children’s Hospital)

  • Alysson R. Muotri

    (University of California San Diego
    Rady Children’s Hospital
    University of California San Diego
    University of California San Diego)

Abstract

Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.

Suggested Citation

  • Fabio Papes & Antonio P. Camargo & Janaina S. Souza & Vinicius M. A. Carvalho & Ryan A. Szeto & Erin LaMontagne & José R. Teixeira & Simoni H. Avansini & Sandra M. Sánchez-Sánchez & Thiago S. Nakahara, 2022. "Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content," Nature Communications, Nature, vol. 13(1), pages 1-26, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29942-w
    DOI: 10.1038/s41467-022-29942-w
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    References listed on IDEAS

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    1. Hreinn Stefansson & Roel A. Ophoff & Stacy Steinberg & Ole A. Andreassen & Sven Cichon & Dan Rujescu & Thomas Werge & Olli P. H. Pietiläinen & Ole Mors & Preben B. Mortensen & Engilbert Sigurdsson & O, 2009. "Common variants conferring risk of schizophrenia," Nature, Nature, vol. 460(7256), pages 744-747, August.
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    3. Junyue Cao & Malte Spielmann & Xiaojie Qiu & Xingfan Huang & Daniel M. Ibrahim & Andrew J. Hill & Fan Zhang & Stefan Mundlos & Lena Christiansen & Frank J. Steemers & Cole Trapnell & Jay Shendure, 2019. "The single-cell transcriptional landscape of mammalian organogenesis," Nature, Nature, vol. 566(7745), pages 496-502, February.
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