Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
EMBO J. 2023 Jun 1;42(11):e110384. doi: 10.15252/embj.2021110384. Epub 2023 Apr 21.
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.
大多数成年海马神经干细胞（NSC）处于静止状态，只有一小部分处于活跃的增殖和神经发生状态。触发从静止到激活转变的分子机制仍知之甚少。在这里，我们发现转录共激活因子 Yap1 的活性在活跃的 NSC 中富集。 Yap1 的基因缺失导致活跃 NSC 的相对比例显著减少，支持 Yap1 在调节从静止到激活的转变中发挥生理作用。野生型 yap1 在成年 NSC 中的过表达不会诱导 NSC 激活，表明存在严格的上游控制机制，但过表达功能获得性突变体（Yap1-5SA）可诱导 NSC 和齿状回星形胶质细胞进入细胞周期。与 yap1 在 NSC 激活中的作用一致，单细胞 RNA 测序显示激活的 NSC 基因表达程序部分诱导。此外，Yap1-5SA 的表达也诱导了 Taz 以及先前在神经胶质瘤干细胞样细胞中鉴定的 yap/Taz 调节子的其他关键成分的表达。因此，失调的 yap1 活性导致海马神经发生受到抑制、细胞分化异常以及部分获得神经胶质瘤干细胞样特征。
