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Role of Yap1 in adult neural stem cell activation

View ORCID ProfileWenqiang Fan, Jerónimo Jurado-Arjona, Gregorio Alanis-Lobato, Sophie Péron, Christian Berger, View ORCID ProfileMiguel A. Andrade-Navarro, View ORCID ProfileSven Falk, View ORCID ProfileBenedikt Berninger
doi: https://doi.org/10.1101/2022.01.12.475985
Wenqiang Fan
1Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • ORCID record for Wenqiang Fan
Jerónimo Jurado-Arjona
1Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom of Great Britain and Northern Ireland
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  • For correspondence: benedikt.berninger@kcl.ac.uk jjurado@kcl.ac.uk
Gregorio Alanis-Lobato
3Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, Germany
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Sophie Péron
1Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom of Great Britain and Northern Ireland
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Christian Berger
4Institute of Genetics, Johannes Gutenberg University Mainz, Mainz, Germany
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Miguel A. Andrade-Navarro
3Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, Germany
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Sven Falk
5Institute of Biochemistry, Friedrich Alexander University Nürnberg-Erlangen, Germany
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Benedikt Berninger
1Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom of Great Britain and Northern Ireland
6MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom of Great Britain and Northern Ireland
7The Francis Crick Institute, United Kingdom of Great Britain and Northern Ireland
8Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Mainz, Germany
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  • ORCID record for Benedikt Berninger
  • For correspondence: benedikt.berninger@kcl.ac.uk jjurado@kcl.ac.uk
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Abstract

Most adult hippocampal neural stem cells (NSCs) remain quiescent with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger eventually the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional activator Yap1 to be enriched in active NSCs. Genetic deletion of Yap1 led to a significant reduction in the relative proportion of active NSCs supporting a physiological role of Yap1 in regulating the transition from quiescence to activation. Overexpression of wild type Yap1 in adult NSCs did not induce NSC activation suggesting tight upstream control mechanisms, but overexpression of a gain-of-function mutant (Yap1-5SA) elicited cell cycle entry in NSCs and hilar astrocytes. Consistent with a role of Yap1 in NSC activation, single cell RNA sequencing revealed the partial induction of an activated NSC gene expression program. Yet, Yap1-5SA expression also induced Taz and other key components of the Yap/Taz regulon previously identified in glioblastoma stem cell-like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, promoting aberrant differentiation instead.

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Posted January 13, 2022.
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Role of Yap1 in adult neural stem cell activation
Wenqiang Fan, Jerónimo Jurado-Arjona, Gregorio Alanis-Lobato, Sophie Péron, Christian Berger, Miguel A. Andrade-Navarro, Sven Falk, Benedikt Berninger
bioRxiv 2022.01.12.475985; doi: https://doi.org/10.1101/2022.01.12.475985
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Role of Yap1 in adult neural stem cell activation
Wenqiang Fan, Jerónimo Jurado-Arjona, Gregorio Alanis-Lobato, Sophie Péron, Christian Berger, Miguel A. Andrade-Navarro, Sven Falk, Benedikt Berninger
bioRxiv 2022.01.12.475985; doi: https://doi.org/10.1101/2022.01.12.475985

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