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

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, Carolina N. Santo, Wei Wu, Hang Yao, Barbara M. P. Araújo, Paulo E. N. F. Velho, Gabriel G. Haddad and Alysson R. Muotri ()
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Fabio Papes: University of Campinas
Antonio P. Camargo: University of Campinas
Janaina S. Souza: University of California San Diego
Vinicius M. A. Carvalho: University of Campinas
Ryan A. Szeto: University of California San Diego
Erin LaMontagne: University of California San Diego
José R. Teixeira: University of Campinas
Simoni H. Avansini: University of California San Diego
Sandra M. Sánchez-Sánchez: University of California San Diego
Thiago S. Nakahara: University of Campinas
Carolina N. Santo: 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
Alysson R. Muotri: University of California San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-26

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29942-w

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