Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content Article Swipe
Fábio Papes
,
Antônio Pedro Camargo
,
Janaína Sena de Souza
,
Vinicius Miessler de Andrade Carvalho
,
Ryan A. Szeto
,
Erin LaMontagne
,
José R. Teixeira
,
Simoni Helena Avansini
,
Sandra M. Sánchez-Sánchez
,
Thiago S. Nakahara
,
Carolina N. Santo
,
Wei Wu
,
Hang Yao
,
Barbara M. P. Araújo
,
Paulo Eduardo Neves Ferreira Velho
,
Gabriel G. Haddad
,
Alysson R. Muotri
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-022-29942-w
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-022-29942-w
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.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41467-022-29942-w
- https://www.nature.com/articles/s41467-022-29942-w.pdf
- OA Status
- gold
- Cited By
- 66
- References
- 72
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4225278364
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4225278364Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s41467-022-29942-wDigital Object Identifier
- Title
-
Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron contentWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2022Year of publication
- Publication date
-
2022-05-02Full publication date if available
- Authors
-
Fábio Papes, Antônio Pedro Camargo, Janaína Sena de Souza, Vinicius Miessler de Andrade Carvalho, Ryan A. Szeto, Erin LaMontagne, José R. Teixeira, Simoni Helena Avansini, Sandra M. Sánchez-Sánchez, Thiago S. Nakahara, Carolina N. Santo, Wei Wu, Hang Yao, Barbara M. P. Araújo, Paulo Eduardo Neves Ferreira Velho, Gabriel G. Haddad, Alysson R. MuotriList of authors in order
- Landing page
-
https://doi.org/10.1038/s41467-022-29942-wPublisher landing page
- PDF URL
-
https://www.nature.com/articles/s41467-022-29942-w.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.nature.com/articles/s41467-022-29942-w.pdfDirect OA link when available
- Concepts
-
Transcription factor, Progenitor cell, Progenitor, Neuron, Loss function, Function (biology), Biology, Cell biology, Neuroscience, Transcription (linguistics), Genetics, Stem cell, Gene, Phenotype, Philosophy, LinguisticsTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
66Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 23, 2024: 16, 2023: 20, 2022: 7Per-year citation counts (last 5 years)
- References (count)
-
72Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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