In a new study, researchers from Germany, Britain and Belgium identified a key protein called Yap1 in the molecular mechanism that triggers neurogenesis in the hippocampus. They found that strict regulation of Yap1 activity is crucial, as its imbalance can lead to tissue damage observed in the early stages of brain cancer. The relevant research results were published online on April 21, 2023 in the EMBO Journal journal, with the title of "The transcriptional co activator Yap1 promotes adult hippocampial neural stem cell activation".
Neurogenesis is a process in which neural stem cells (NSCs) in the brain produce new neurons. Neurogenesis is a key process in embryonic development, but it also continues in some brain regions after birth and throughout adulthood. In adulthood, neurogenesis is mainly responsible for brain plasticity.
In the adult hippocampus, a brain region responsible for memory and learning, most stem cells remain stationary. This reversible suspension protects stem cells from damage and controls the rate of neurogenesis. If necessary, these stem cells can detach from this suspended state and undergo activation. The mechanism of controlling stillness and activation is not yet fully understood.
These authors attempted to understand the mechanism of neurogenesis in the adult hippocampus. When analyzing RNA sequencing data, they found that Yap1 was enriched in activated NSCs. This observation prompted them to conduct in-depth investigations into the role of Yap1.
They used primary cell cultures from adult hippocampus tissue, a proven model for studying the transition between quiescent and active NSCs. They confirmed that the transfer of Yap1 from cytoplasm to nucleus is accompanied by the activation of NSC, while the opposite occurs when NSC returns to a resting state.
They then searched for the consequences of abnormal levels of Yap1 protein in the body. Although the short-term impact is not significant, after excluding Yap1 protein, the long-term activation rate of NSC decreases. This confirms that the activation of NSC is influenced by Yap1, while other compensation mechanisms remain to be determined.
The next step is to observe the consequences of excessive expression of Yap1. Interestingly, overexpression of Yap1 does not induce activation, indicating a very strict upstream control. In order to disrupt this control, they overexpressed a Yap1 mutant protein that is resistant to phosphorylation (a protein modification). They observed that this indeed promotes activation, indicating that phosphorylation is involved in the upstream control mechanism of Yap1.
The overexpression of this Yap1 mutant protein also induces the expression of other proteins associated with glioblastoma. As is well known, this type of brain tumor grows rapidly and is highly invasive. In fact, the long-term expression of Yap1 mutant protein has caused large-scale damage to brain tissue. This finding suggests that the loss of control over Yap1 may be a critical step in the initiation of brain tumors.
These authors point out that this finding is worth further exploring the role of Yap1 in adult neurogenesis, especially during aging and brain cancer.
Professor Benedikt Berninger, the co corresponding author of the paper, said, "We hope our research will help uncover the mystery of the mechanism that controls the activity of neural stem cells in the adult brain, especially in the aging brain, and may enable us to develop new strategies to defeat deadly brain cancer stem cells."
