Animal model used by researchers from the University of Tsukuba identifies the mechanism of glial cells in brain development.
Both neuronal and non-neuronal cells communicate during normal brain development. These non-neuronal cells are also known as glial cells. In a recently published study, it was discovered that the protein arginine methyltransferase 1 (PRMT1) is involved in the molecular mechanism by which glial cells interact and affect proper brain development.
PRMTs are a family of proteins that mediates methylation of the amino acid, arginine, in histone and non-histone proteins. This process is key in regulating cellular functions, for survival, proliferation, and development. There are three main types of PRMTs based on its function, namely promotion of mono-methylation, asymmetric, and non-symmetric demethylation. PRMT1 is one of the most well-known of the family and controls tissue development and lifespan. It is also known to trigger stress response pathways when required.
Removal of PRMT1 was shown to result in the loss of the protein in all tissues during development, resulting in disruptions in embryonic development. Tissue-specific elimination of PRMT1 has been of increasing research interest to understand the mechanism that it affects in tissue development and function.
"We previously discovered that PRMT1 is critical for the function of one type of glial cell, oligodendrocytes, during brain development," says corresponding author of the study Professor Akiyoshi Fukamizu. "The goal of this study was to understand how other glial cells may contribute to the hypomyelination phenotype we observe in PRMT1 conditional knockout mice."
Using the same mouse model as in the research team’s previous study, they set out to comprehend how PRMT1 is involved in glial cell function in brain development. PRMT1 was eliminated in mice in the neural stem cells as well as the cells that were derived from neural stem cells. These cells include oligodendrocytes and astrocytes, expect microglia, which are key glial cell types in the brain.
The researchers performed RNA-sequencing of the outer region of the brain, called the cortex, where these cells reside in neonatal PRMT1 knockout mice. They were then able to survey changes in gene expression in the brain of mice lacking PRMT1. Interestingly, the researchers found increased expression of genes regulating inflammation, pointing towards the involvement of astrocytes and microglia. Looking closer at markers of inflammation, the researchers found that among a panel of inflammation markers the expression of Interleukin-6 in particular was significantly increased in mice without PRMT1.
The team then went in further to examine the reason behind the increase in inflammation in the brain of PRMT1 eliminated neonatal mice and zooming in at astrocytes and microglia. Studying the biomarkers of astrocytes and microglia, they identified signs of severe ongoing inflammation. An increase in astrocyte and microglia cells were observed, this is known as massive astrogliosis. The increase in microglia was of particular interest as they are not derived from neural stem cells and had normal expression of PRMT1.
"These are striking results that show how a single protein controls such essential developmental processes in the brain. Our results provide a novel insight into the molecular control of brain development," says first author of the study Assistant Professor Misuzu Hashimoto (Gifu University).