TY - JOUR
T1 - The transcriptional co-activator Yap1 promotes adult hippocampal neural stem cell activation
AU - Fan, Wenqiang
AU - Jurado Arjona, Jeronimo
AU - Alanis-Lobato, Gregorio
AU - Peron, Sophie
AU - Berger, Christian
AU - Andrade-Navarro, Miguel A
AU - Falk, Sven
AU - Berninger, Benedikt
N1 - Funding Information:
This research was funded in part by the Wellcome Trust (206410/Z/17/Z) to BB. For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. This study was also supported by funding from the German Research Foundation (DFG, CRC1080, project number 221828878, CRC1193 project number 26410226) to BB; core funding to the Francis Crick Institute from Cancer Research UK, The Medical Research Council and the Wellcome Trust (FC001002); funding from the Naturwissenschaftlich-Medizinischen Forschungszentrum (NMFZ2016) of the Johannes Gutenberg University Mainz to CB. JJ-A was supported by research fellowships from Fundación Alfonso Martín Escudero, Fundación Ramón Areces, and the European Commission (MSCA-IF-841260). We are grateful to Flow Cytometry Core Facility, Genomic Core Facility, Microscopy Core Facility, and Bioinformatics Core Facility of the Institute of Molecular Biology (IMB) Mainz for their support regarding single cell RNA-sequencing experiments and raw data processing. Parts of the schematic diagram were created with BioRender.com. Open Access funding enabled and organized by Projekt DEAL.
Funding Information:
This research was funded in part by the Wellcome Trust (206410/Z/17/Z) to BB. For the purpose of open access, the author has applied a CC BY public copyright license to any author‐accepted manuscript version arising from this submission. This study was also supported by funding from the German Research Foundation (DFG, CRC1080, project number 221828878, CRC1193 project number 26410226) to BB; core funding to the Francis Crick Institute from Cancer Research UK, The Medical Research Council and the Wellcome Trust (FC001002); funding from the Naturwissenschaftlich‐Medizinischen Forschungszentrum (NMFZ2016) of the Johannes Gutenberg University Mainz to CB. JJ‐A was supported by research fellowships from Fundación Alfonso Martín Escudero, Fundación Ramón Areces, and the European Commission (MSCA‐IF‐841260). We are grateful to Flow Cytometry Core Facility, Genomic Core Facility, Microscopy Core Facility, and Bioinformatics Core Facility of the Institute of Molecular Biology (IMB) Mainz for their support regarding single cell RNA‐sequencing experiments and raw data processing. Parts of the schematic diagram were created with BioRender.com . Open Access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - Most 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 Yap1activity led to repression of hippocampal neurogenesis, aberrant cell differentiation, and partial acquisition of a glioblastoma stem cell-like signature.
AB - Most 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 Yap1activity led to repression of hippocampal neurogenesis, aberrant cell differentiation, and partial acquisition of a glioblastoma stem cell-like signature.
UR - http://www.scopus.com/inward/record.url?scp=85153520006&partnerID=8YFLogxK
U2 - DOI: 10.15252/embj.2021110384
DO - DOI: 10.15252/embj.2021110384
M3 - Article
SN - 0261-4189
VL - 42
JO - The EMBO journal
JF - The EMBO journal
IS - 11
M1 - e110384
ER -