Scientists studying an enzyme in fruit fly larvae report that they have found that it plays an important role in waking up brain stem cells from their dormant quiescent state, enabling them to proliferate and generate new neurons. The Duke-NUS Medical School, Singapore team, which published its study “Histone lysine methyltransferase Pr‐set7/SETD8 promotes neural stem cell reactivation,” in EMBO Reports, says their work could help clarify how some neurological disorders such as autism and microcephaly occur.
“The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggests that variants of histone lysine methyltransferases including KMT5A are associated with neurodevelopmental disorders. However, the function of KMT5A/Pr‐set7/SETD8 in the central nervous system is not well established,” write the investigators.
“Here, we show that Drosophila Pr‐Set7 is a novel regulator of NSC reactivation. Loss of function of pr‐set7 causes a delay in NSC reactivation and loss of H4K20 monomethylation in the brain. Through NSC‐specific in vivo profiling, we demonstrate that Pr‐set7 binds to the promoter region of cyclin‐dependent kinase 1 (cdk1) and Wnt pathway transcriptional co‐activator earthbound1/jerky (ebd1). Further validation indicates that Pr‐set7 is required for the expression of cdk1 and ebd1 in the brain. Similar to Pr‐set7, Cdk1 and Ebd1 promote NSC reactivation.
“Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr‐set7‐depleted brains. Therefore, Pr‐set7 promotes NSC reactivation by regulating Wnt signaling and cell cycle progression. Our findings may contribute to the understanding of mammalian KMT5A/PR‐SET7/SETD8 during brain development.”
Pr-set7 is an enzyme involved in maintaining genome stability, DNA repair and cell cycle regulation, as well as turning various genes on or off. This protein, which goes by a few different names, has remained largely unchanged as species have evolved. Wang Hongyan, PhD, a professor and deputy director at Duke-NUS’ Neuroscience and Behavioral Disorders Program, and her colleagues set out to understand the protein’s function during brain development.
“Genetic variants of the human version of Pr-set7 are associated with neurodevelopmental disorders, with typical symptoms including intellectual disability, seizures and developmental delay,” explained Wang. “Our study is the first to show that Pr-set7 promotes neural stem cell reactivation and, therefore, plays an important role in brain development.”
Neural stem cells normally oscillate between states of quiescence and proliferation. Maintaining an equilibrium between the two is very important. Most neural stem cells are quiescent in adult mammalian brains. They are reactivated to generate new neurons in response to stimuli, such as injury, the presence of nutrients or exercise.
However, neural stem cells gradually lose their capacity to proliferate with age and in response to stress, and anxiety.
Wang and her colleagues studied what happened when the gene coding for Pr-set7 is turned off in larval fruit fly brains. They found it caused a delay in the reactivation of neural stem cells from their quiescent state. To reactivate neural stem cells, Pr-set7 needs to turn on at least two genes: cyclin-dependent kinase 1 (cdk1) and earthbound 1 (Ebd1).
The scientists found that overexpressing the proteins coded by these genes led to the reactivation of neural stem cells even when the Pr-set7 gene was turned off. These findings show that Pr-set7 binds to the cdk1 and Ebd1 genes to activate a signaling pathway that reactivates neural stem cells from their quiescent state, according to Wang.
“Since Pr-set7 is conserved across species, our findings could contribute to the understanding of the roles of its mammalian counterpart in neural stem cell proliferation and its associated neurodevelopmental disorders,” she said.
“With this latest study, Professor Wang’s fundamental research in neuroscience has yielded valuable insights into several neurodevelopmental disorders; insights that have the potential to improve the way we care for people with such disorders,” noted Patrick Casey, PhD, senior vice-dean for research, Duke-NUS.
The scientists are now extrapolating this study to understand the roles of the mammalian and human forms of Pr-set7, called SETD8 and KMT5A respectively, in brain development.