Coactivator‐associated arginine methyltransferase 1 controls oligodendrocyte differentiation in the corpus callosum during early brain development

Abstract

Protein arginine methylation has been recognized as one of key posttranslational modifications for refined protein functions, mediated by protein arginine methyltransferases (Prmts). Coactivator-associated arginine methyltransferase (Carm1, also known as Prmt4) participates in various cellular events, such as cell survival, proliferation, and differentiation through its protein arginine methylation activities. Carm1 regulates cell proliferation of a neuronal cell line and is reportedly expressed in the mammalian brain. However, its detailed function in the central nervous system, particularly in glial cells, remains largely unexplored. In this study, Carm1 exhibited relatively high expression in oligodendrocyte (OL) lineage cells present in the corpus callosum of the developing brain, followed by a remarkable downregulation after active myelination. The suppression of Carm1 activity by inhibitors in isolated oligodendrocyte precursor cells (OPCs) reduced the number of Ki67-expressing and BrdU-incorporated proliferating cells. Furthermore, Carm1 inactivation attenuated OL differentiation, as determined by the expression of Plp, a reliable myelin-related marker. It also impaired the extension of OL processes, accompanied by a significant reduction in gene expression related to OL differentiation and myelination, such as Sox10, Cnp, Myrf, and Mbp. In addition, OLs co-cultured with embryonic dorsal root ganglia neurons demonstrated that Carm1 activity is required for the appropriate formation of myelin processes and myelin sheaths around neuronal axons, and the induction of the clustering of Caspr, a node of Ranvier structural molecule. Thus, we propose that Carm1 is an essential molecule for the development of OPCs and OLs during brain development.

Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in Alzheimer's disease

“…The expression of PRMT4 could be reduced in a dose‐dependent manner with the administration of TP‐064 (Figure 1e). Others have reported that PRMT 4 is expressed in the central nervous system (Ishino et al, 2022), and as PRMT4 is a type‐1 PRMT, it produces ADMA (Blanc & Richard, 2017). Our findings suggest that ADMA production is enhanced in the serum of 3xTg‐AD mice (Figure 3a).…”

Oligodendrocytes: From Their Development to Function and Dysfunction

“…Advancing age is the single most prominent risk factor for NDDs. Although studies of OPC proliferation and differentiation in the developing nervous system have suggested a number of pathways that can be targeted to enhance remyelination in the mature nervous system (Fancy et al, 2011;Ishino et al, 2022), increasing evidence suggests that young and old OPCs are not identical (Segel et al, 2019;de la Fuente et al, 2020). In fact, a substantial loss of myelinated fibers occurs with aging (Marner et al, 2003), and remyelination is thought to be one of the major processes in the brain affected by aging (Sim et al, 2002;Neumann et al, 2019).…”

Functions and dysfunctions of oligodendrocytes in neurodegenerative diseases

“…Advancing age is the single most prominent risk factor for NDDs. Although studies of OPC proliferation and differentiation in the developing nervous system have suggested a number of pathways that can be targeted to enhance remyelination in the mature nervous system ( Fancy et al, 2011 ; Ishino et al, 2022 ), increasing evidence suggests that young and old OPCs are not identical ( Segel et al, 2019 ; de la Fuente et al, 2020 ). In fact, a substantial loss of myelinated fibers occurs with aging ( Marner et al, 2003 ), and remyelination is thought to be one of the major processes in the brain affected by aging ( Sim et al, 2002 ; Neumann et al, 2019 ).…”