TY - JOUR
T1 - scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse
AU - Wittmann, Marie Theres
AU - Katada, Sayako
AU - Sock, Elisabeth
AU - Kirchner, Philipp
AU - Ekici, Arif B.
AU - Wegner, Michael
AU - Nakashima, Kinichi
AU - Lie, Dieter Chichung
AU - Reis, André
N1 - Funding Information:
We thank Sven Falk, Silvia Cappello and all members of the Institutes of Human Genetics and Biochemistry for helpful discussions. We thank Tõnis Timmusk for the kind gift of pcDNA3-plasmid for TCF4A and TCF4B isoforms. Microscopy/image analysis was performed with support from a grant from the DFG (INST 410/45-1 FUGG).
Funding Information:
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; 270949263/GRK2162 and LI 858/9-1), by the Interdisciplinary Centre for Clinical Research Erlangen (Interdisziplin?res Zentrum f?r Klinische Forschung, Universit?tsklinikum Erlangen; E16 to D.C.L. and A.R.), and Bavarian Research Association: Interaction of human brain cells (ForInter) funded by Bavarian State Ministry of Science and the Arts (Bayerisches Staatsministerium f?r Wissenschaft, Forschung und Kunst; D.C.L.). M.T.W. is member of the research training group 2162 ?Neurodevelopment and Vulnerability of the Central Nervous System? of the Deutsche Forschungsgemeinschaft (DFG GRK2162/1). Open access funding provided by Friedrich-Alexander University Erlangen-Nuernberg. Deposited in PMC for immediate release.
Funding Information:
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; 270949263/GRK2162 and LI 858/9-1), by the Interdisciplinary Centre for Clinical Research Erlangen (Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Erlangen; E16 to D.C.L. and A.R.), and Bavarian Research Association: Interaction of human brain cells (ForInter) funded by Bavarian State Ministry of Science and the Arts (Bayerisches Staatsministerium für Wissenschaft, Forschung und Kunst; D.C.L.). M.T.W. is member of the research training group 2162 ‘Neurodevelopment and Vulnerability of the Central Nervous System’ of the Deutsche Forschungsgemeinschaft (DFG GRK2162/1). Open access funding provided by Friedrich-Alexander University Erlangen-Nuernberg. Deposited in PMC for immediate release.
Publisher Copyright:
© 2021. Published by The Company of Biologists Ltd
PY - 2021/7
Y1 - 2021/7
N2 - Transcription factor 4 (TCF4) is a crucial regulator of neurodevelopment and has been linked to the pathogenesis of autism, intellectual disability and schizophrenia. As a class I bHLH transcription factor (TF), it is assumed that TCF4 exerts its neurodevelopmental functions through dimerization with proneural class II bHLH TFs. Here, we aim to identify TF partners of TCF4 in the control of interhemispheric connectivity formation. Using a new bioinformatic strategy integrating TF expression levels and regulon activities from single cell RNA-sequencing data, we find evidence that TCF4 interacts with non-bHLH TFs and modulates their transcriptional activity in Satb2+ intercortical projection neurons. Notably, this network comprises regulators linked to the pathogenesis of neurodevelopmental disorders, e.g. FOXG1, SOX11 and BRG1. In support of the functional interaction of TCF4 with non-bHLH TFs, we find that TCF4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implicated in this process. In addition to identifying new candidate interactors of TCF4 in neurodevelopment, this study illustrates how scRNA-Seq data can be leveraged to predict TF networks in neurodevelopmental processes.
AB - Transcription factor 4 (TCF4) is a crucial regulator of neurodevelopment and has been linked to the pathogenesis of autism, intellectual disability and schizophrenia. As a class I bHLH transcription factor (TF), it is assumed that TCF4 exerts its neurodevelopmental functions through dimerization with proneural class II bHLH TFs. Here, we aim to identify TF partners of TCF4 in the control of interhemispheric connectivity formation. Using a new bioinformatic strategy integrating TF expression levels and regulon activities from single cell RNA-sequencing data, we find evidence that TCF4 interacts with non-bHLH TFs and modulates their transcriptional activity in Satb2+ intercortical projection neurons. Notably, this network comprises regulators linked to the pathogenesis of neurodevelopmental disorders, e.g. FOXG1, SOX11 and BRG1. In support of the functional interaction of TCF4 with non-bHLH TFs, we find that TCF4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implicated in this process. In addition to identifying new candidate interactors of TCF4 in neurodevelopment, this study illustrates how scRNA-Seq data can be leveraged to predict TF networks in neurodevelopmental processes.
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U2 - 10.1242/DEV.196022
DO - 10.1242/DEV.196022
M3 - Article
C2 - 34184026
AN - SCOPUS:85111628519
VL - 148
JO - Journal of Embryology and Experimental Morphology
JF - Journal of Embryology and Experimental Morphology
SN - 0950-1991
IS - 14
M1 - dev196022
ER -