14/04/23
During embryonic development, neural stem cells (NSCs) migrate from the dentate epithelium to settle in the dentate gyrus anlage of the hippocampus. Most of these hippocampal NSCs remain quiescent but some will undergo proliferation and neurogenesis. Although we are beginning to understand more about quiescence and activation, the mechanisms controlling this transition remain a big mystery in adult NSC biology.
As well as giving us insights into fundamental biological questions, understanding these mechanisms and regulation of the transition promises important new insights into glioblastoma formation and tumourigenesis.
In exciting new work published in The EMBO Journal, Benedikt Berninger (CDN, University Medical Center Mainz, and University of Erlangen-Nuremberg), Wenqiang Fan and colleagues, including CDN colleague Jerónimo Jurado-Arjona, addressed this question. Examining active NSCs in the adult hippocampus, Fan et al. found increased activity of the transcriptional coactivator Yap1. The authors then deleted Yap1 to understand the gene’s role in the regulation of the transition from quiescence to activation. They found that the deletion of the gene compromises NSC activation, with fewer active NSCs observed. Fan et al. next examined the effect of Yap1 gain-of-function on the activation of NSCs by overexpressing constitutively active Yap1 in adult NSCs. Interestingly, this led to robust cell cycle entry of quiescent NSCs Consistent with the gene playing an important role in NSC activation, single cell RNA sequencing revealed a partial induction of an activated NSC gene expression programme. However, Yap1 gain-of-function also induced expression of Taz and other key components identified in glioblastoma stem cell-like cells. Indeed, the authors found that prolonged Yap1 activity in adult hippocampal NSCs disrupted physiological neurogenesis, promoting instead aberrant cell differentiation and partial acquisition of a glioblastoma stem cell-like signature.
Fan et al.’s findings, in addition to furthering our understanding of a key biological process, have important implications for our understanding of early tumourigenesis and, in particular, the development of glioblastomas. The authors indicate that future work could help us understand whether dysregulation of Yap1, which is normally tightly regulated, induces the conversion of adult NSCs or post mitotic astrocytes into deadly glioblastoma stem cell-like cells.
