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

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 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.

SUBMITTER: Fan W

PROVIDER: S-EPMC10233373 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Fan Wenqiang W Jurado-Arjona Jerónimo J Alanis-Lobato Gregorio G Péron Sophie S Berger Christian C Andrade-Navarro Miguel A MA Falk Sven S Berninger Benedikt B

The EMBO journal 20230421 11

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 regu ...[more]

PMID: 37083045

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Project description:Adult radial glia-like cells (RGLs) residing in the subgranular zone (SGZ) of the dentate gyrus (DG) are finely regulated to control the generation of new neurons. Quiescence is essential for the long-term maintenance of the RGL pool. Intrinsic factors as well as extrinsic niche signals orchestrate the balance between RGL quiescence and activation, but the mechanisms are still not completely understood. Yap1, a core factor of Hippo signaling, is very important for the proliferation of stem cells of various organs and species, such as intestinal stem cells of the mouse and neural stem cells in Drosophila brain. Here I addressed the role of Yap1 in adult hippocampal neurogenesis by gain- and loss-of-function studies. I found that the expression of Yap1 was enriched in adult RGLs, but was undetectable in other cell types such as neurons and cells of the oligodendroglial lineage. Through the analysis of conditional knock-out of Yap1 in adult RGLs and their lineage, I found that fewer RGLs became activated while a significantly higher proportion of RGLs remained in the quiescent state. Conversely, overexpression of constitutively active mutant variant of Yap1 (Yap1 5SA) induced the proliferation of quiescent RGLs in vitro and in vivo. This effect was dependent on functional interaction with the TEA Domain Transcription Factor (TEAD). Pharmacological blocking the interaction between endogenous Yap1 and TEAD by verteporfin reduced the rate of proliferation of neural progenitors in vitro, which indicates a physiological role of Yap1-TEAD interaction in regulating the transition between quiescence and activation. Interestingly, constitutive expression of Yap1 5SA in RGLs blocked adult neurogenesis and retained the cells in a progenitor-like (Sox2+) state. To further explore the molecular mechanisms of Yap1 in regulating the activation of quiescent RGLs, single-cell RNA sequencing analysis was performed at 3 and 7 days following Yap1 5SA overexpression. Yap1 5SA overexpressing cells exhibited increased signature of active NSCs but also displayed distinct features such as epithelial-to-mesenchymal transition (EMT). Importantly, we found that Catenin Beta 1 (CTNNB1) was upregulated suggesting a potential involvement of Wnt signaling in the proliferative effect of Yap1 5SA overexpression in adult NSCs. In sum, this work provides compelling evidence for regulation of the balance between activation and quiescence of adult hippocampal RGLs by Yap1.

Project description:Over the last years, the SWATH data-independent acquisition protocol (Sequential Window acquisition of All THeoretical mass spectra) has become a cornerstone for the worldwide proteomics community (Collins et al., 2017) [1]. In this approach, a high-resolution quadrupole-ToF mass spectrometer acquires thousands of MS/MS data by selecting not just a single precursor at a time, but by allowing a broad m/z range to be fragmented. This acquisition window is then sequentially moved from the lowest to the highest mass selection range. This technique enables the acquisition of thousands of high-resolution MS/MS spectra per minute in a standard LC-MS run. In the subsequent data analysis phase, the corresponding dataset is searched in a "triple quadrupole-like" mode, thus not considering the whole MS/MS scan spectrum, but by searching for several precursor to fragment transitions that identify and quantify the corresponding peptide. This search is made possible with the use of an ion library, previously acquired in a classical data dependent, full-spectrum mode (Fabre et al., 2017; Wu et al., 2017) [2], [3]. The SWATH protocol, combining the protein identification power of high-resolution MS/MS spectra with the robustness and accuracy in analyte quantification of triple-quad targeted workflows, has become very popular in proteomics research. The major drawback lies in the ion library itself, which is normally demanding and time-consuming to build. Conversely, through the realignment of chromatographic retention times, an ion library of a given proteome can relatively easily be tailored upon "any" proteomics experiment done on the same proteome. We are thus hereby sharing with the worldwide proteomics community our newly acquired ion library of mouse adult hippocampal neural stem cells. Given the growing effort in neuroscience research involving proteomics experiments (Pons-Espinal et al., 2017; Sarnyai and Guest, 2017; Sethi et al., 2015; Bramini et al., 2016) [4,[5], [6], [7], we believe that this data might be of great help for the neuroscience community. All the here reported data (RAW files, results and ion library) can be freely downloaded from the SWATHATLAS (Deutsch et al., 2008) [8] website (http://www.peptideatlas.org/PASS/PASS01110).

Dataset Information

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

Publications

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

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