Yap1 protein identified as key to neurogenesis in the hippocampus and brain cancer initiation

Today, a new study published in The EMBO Journal sheds light on a crucial protein involved in the process of neurogenesis in the hippocampus. The researchers found that strict regulation of Yap1 activity is crucial, as any dysregulation can lead to tissue disruption similar to the early stages of brain cancer.

Neurogenesis is the process through which new neurons are generated by neural stem cells (NSCs) in the brain. It is a crucial process in embryo development and continues in certain brain regions even after birth and throughout adulthood. In adulthood, neurogenesis is responsible for brain plasticity.

In the adult hippocampus, a vital brain region responsible for learning and memory, most stem cells are in a state of quiescence, protecting them from damage and controlling the rate of neurogenesis. When required, these stem cells can be activated to produce new neurons. However, the mechanisms that control quiescence and activation are not entirely understood.

Researchers at the Center for Developmental Neurobiology wanted to investigate the underlying mechanism of neurogenesis in the adult hippocampus. Upon analyzing RNA sequencing data, they discovered that Yap1 is abundant in activated NSCs. This finding prompted a more in-depth study of Yap1’s role.

The researchers used primary cell culture from adult hippocampal tissue, a proven model for investigating the transition between NSC states of quiescence and activation. They confirmed that the transfer of Yap1 from the cytoplasm to the nucleus occurs during NSC activation, with the reverse happening as the NSCs return to quiescence.

The researchers then investigated the consequences of abnormal Yap1 protein levels in vivo. Although the short-term effect was minor, long-term deletion of the Yap1 protein reduced NSC activation, confirming that Yap1 plays a role in NSC activation, with other compensatory mechanisms still to be identified.

The next step was to examine the effects of Yap1 overexpression. Interestingly, overexpressing Yap1 did not induce activation, indicating that tight upstream control mechanisms are in place. To bypass this control, the researchers overexpressed a mutant Yap1 protein that is resistant to phosphorylation, a type of protein modification. They found that this mutant protein promotes activation, indicating that phosphorylation is involved in the upstream control mechanism of Yap1.

Overexpressing this mutant Yap1 protein also led to the expression of other proteins linked to glioblastoma, a fast-growing and highly aggressive brain tumor. In fact, long-term expression of the mutant Yap1 caused extensive disruption of brain tissue, suggesting that loss of Yap1 control could be a critical step in the initiation of brain tumors.

The authors of the study noted that these findings warrant further investigation into Yap1 in adult neurogenesis, particularly during aging and brain cancer.

“We hope our study sheds light on the mechanisms that control neural stem cell activity in the adult and aging brain and may help us develop new strategies to combat deadly brain cancer stem cells,” said Professor Benedikt Berninger, the lead author of the study.

Source: King’s College London

Leave a Comment