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

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 fibroblast...

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Main Authors: Araújo, B.M.P (Author), Avansini, S.H (Author), Camargo, A.P (Author), Carvalho, V.M.A (Author), de Souza, J.S (Author), Haddad, G.G (Author), LaMontagne, E. (Author), Muotri, A.R (Author), Nakahara, T.S (Author), Papes, F. (Author), Sánchez-Sánchez, S.M (Author), Santo, C.N (Author), Szeto, R.A (Author), Teixeira, J.R (Author), Velho, P.E.N.F (Author), Wu, W. (Author), Yao, H. (Author)
Format: Article
Language:English
Published: Nature Research 2022
Online Access:View Fulltext in Publisher
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001 10.1038-s41467-022-29942-w
008 220706s2022 CNT 000 0 und d
020 |a 20411723 (ISSN) 
245 1 0 |a Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content 
260 0 |b Nature Research  |c 2022 
856 |z View Fulltext in Publisher  |u https://doi.org/10.1038/s41467-022-29942-w 
520 3 |a 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. © 2022, The Author(s). 
700 1 0 |a Araújo, B.M.P.  |e author 
700 1 0 |a Avansini, S.H.  |e author 
700 1 0 |a Camargo, A.P.  |e author 
700 1 0 |a Carvalho, V.M.A.  |e author 
700 1 0 |a de Souza, J.S.  |e author 
700 1 0 |a Haddad, G.G.  |e author 
700 1 0 |a LaMontagne, E.  |e author 
700 1 0 |a Muotri, A.R.  |e author 
700 1 0 |a Nakahara, T.S.  |e author 
700 1 0 |a Papes, F.  |e author 
700 1 0 |a Sánchez-Sánchez, S.M.  |e author 
700 1 0 |a Santo, C.N.  |e author 
700 1 0 |a Szeto, R.A.  |e author 
700 1 0 |a Teixeira, J.R.  |e author 
700 1 0 |a Velho, P.E.N.F.  |e author 
700 1 0 |a Wu, W.  |e author 
700 1 0 |a Yao, H.  |e author 
773 |t Nature Communications