The transcriptional co‐activator Yap1 promotes adult hippocampal neural stem cell activation

Author:

Fan Wenqiang1ORCID,Jurado‐Arjona Jerónimo12ORCID,Alanis‐Lobato Gregorio3,Péron Sophie12,Berger Christian4,Andrade‐Navarro Miguel A3ORCID,Falk Sven5ORCID,Berninger Benedikt12678ORCID

Affiliation:

1. Institute of Physiological Chemistry University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany

2. Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience King's College London London UK

3. Faculty of Biology Johannes Gutenberg University Mainz Mainz Germany

4. Institute of Genetics Johannes Gutenberg University Mainz Mainz Germany

5. Institute of Biochemistry Friedrich‐Alexander‐Universität Nürnberg‐Erlangen Erlangen Germany

6. MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology & Neuroscience King's College London London UK

7. The Francis Crick Institute London UK

8. Focus Program Translational Neuroscience Johannes Gutenberg University Mainz Mainz Germany

Abstract

AbstractMost adult hippocampal neural stem cells (NSCs) remain quiescent, with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional co‐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 a partial induction of an activated NSC gene expression program. Furthermore, Yap1‐5SA expression also induced expression of Taz and other key components of the Yap/Taz regulon that were previously identified in glioblastoma stem cell‐like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, aberrant cell differentiation, and partial acquisition of a glioblastoma stem cell‐like signature.

Funder

Deutsche Forschungsgemeinschaft

European Commission

Fundación Alfonso Martín Escudero

Federal Railroad Administration

Johannes Gutenberg-Universität Mainz

Wellcome Trust

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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