Neurogenesis is the process by which neural stem cells (NSCs) in the brain generate new neurons. Neurogenesis is a critical process in embryonic development, but it also continues after birth in certain brain regions and throughout adulthood. During adulthood, neurogenesis is primarily responsible for brain plasticity.
In the adult hippocampus, a brain region responsible for memory and learning, most stem cells are in a quiescent state. This reversible pause protects stem cells from damage and controls the rate of neurogenesis. Stem cells can be taken out of this pause to activate when necessary. The mechanisms controlling quiescence and activation are still not fully understood.
A new article published recently in The EMBO Journal identifies a key protein in the molecular machinery that triggers neurogenesis in the hippocampus. They found that tight regulation of Yap1 activity is essential because dysregulation leads to tissue destruction in the early stages of brain cancer.
Researchers at the Center for Developmental Neurobiology sought to understand the mechanisms of neurogenesis in the adult hippocampus. After analyzing RNA-sequencing data, they found that Yap1 was enriched in activated NSCs. This observation prompted in-depth investigations into the role of Yap1.
They used primary cell cultures from adult hippocampal tissue, a validated model for studying the transition of NSCs between quiescent and activated states. They demonstrated that the transfer of Yap1 from the cytoplasm to the nucleus was accompanied by the activation of NSCs, whereas the opposite occurred when NSCs returned to quiescence.
They then looked for the consequences of abnormal Yap1 protein levels in the body. Although the short-term effects were small, deletion of the Yap1 protein reduced the activation of NSCs in the long-term. This confirms that the activation of NSCs is affected by Yap1, and other compensatory mechanisms have yet to be identified.
The next step is to look at the consequences of Yap1 overexpression. Interestingly, overexpression of Yap1 did not induce activation, suggesting a very tight upstream control. To override this control, they overexpressed a mutant Yap1 protein that was resistant to phosphorylation, a modification of the protein. This, they observed, did promote activation, suggesting that phosphorylation is involved in an upstream control mechanism of Yap1.
Overexpression of this mutant Yap1 protein also induced the expression of other proteins associated with glioblastoma. This type of brain tumor grows quickly and is very aggressive. Indeed, long-term expression of the Yap1 mutant resulted in massive disruption of brain tissue. This finding suggests that loss of control of Yap1 may be a critical step in brain tumorigenesis.
The authors note that this finding warrants further investigation of the role of Yap1 in adult neurogenesis, particularly during aging and brain cancer.
Professor Benedikt Berninger, lead author of the study, said: “We hope that our research will help to unravel the mystery surrounding the mechanisms that control the activity of neural stem cells in adults, especially the aging brain, and may allow us to develop new strategies to defeat lethal brain cancer stem cells.”