Mini ReviewRoles of protein arginine methyltransferase 1 (PRMT1) in brain development and disease
Introduction
Protein arginine methylation, a posttranslational modification recognized to be as important as phosphorylation or ubiquitination, is catalyzed by nine members of the protein arginine methyltransferase family (PRMT1–9) (Fig. 1). PRMTs are classified into type I, II, and III, depending on the modes of methylation (Fig. 1). All PRMTs catalyze mono-methylation of guanidino nitrogen atoms of arginine residues by using S-adenosylmethionine (SAM) as a methyl donor. However, only type I and II PRMTs further catalyze dimethylation of the mono-methylated arginine. The difference between type I and II is that type I PRMTs (PRMT1, 2, 3, 6, 8, and CARM1) form an asymmetric dimethyl arginine (ADMA), while type II PRMTs (PRMT5 and 9) form a symmetric dimethyl arginine (SDMA). Among type I PRMTs, PRMT1 is responsible for the biosynthesis of 85% of ADMA in mammals [1]. In contrast, type III PRMT (PRMT7) is only known for its monomethylation activity due to its unique structural features.
Protein arginine methylation has been implicated in many cellular processes such as transcription, signal transduction, cellular survival, DNA damage response, RNA processing, and transport or inflammatory responses [2,3]. The effects of arginine methylation on protein functions vary depending on the target proteins; therefore, arginine methylation does not serve as a simple switch for a certain functional change. Substrate specificity varies among PRMTs, and some members (PRMT1, 3, and 6) frequently target glycine-arginine-rich motifs on proteins. Regarding PRMT1, which is the main focus of this review, dozens of substrates (histone and non-histone proteins) have so far been identified. As the predominant type I PRMT, general roles of PRMT1 have been uncovered in conventional cultured cells. However, the in vivo physiological and pathological importance of PRMT1 in the central nervous system (CNS) remains largely unexplored.
Systemic knockout of PRMT1 results in early embryonic lethality [by embryonic day (E) 7.5], suggesting that PRMT1 is essential for embryonic development [4]. Although the reason for early death has not been uncovered, it suggests that PRMT1 is required for some postimplantation events. A growing number of studies from our and other research groups have identified tissue-specific functions of PRMT1 [5,6]. For example, PRMT1 is essential for embryonic vascular development [5] and normal heart function [6].
Although PRMT1 exhibits ubiquitous distribution throughout the body, its expression is first observed in the developing CNS and then spreads to all the major brain areas of the adult CNS [4]. Most of the PRMT family members, including PRMT1, 2, 3, 5, 7, 8 and CARM1, were confirmed to be expressed in the mouse brain by Western blot and/or immunohistochemistry [[7], [8], [9], [10], [11], [12]], and special attentions have been paid to hippocampal expression of PRMT3, 7 and 8. Notably, PRMT8 is a brain-specific member of type I PRMTs, and its expression increases after birth peaking at postnatal day(P) 21 in the hippocampus [12]. Compared to other PRMTs, expression of PRMT1 is seen at earlier stages in development, which implies its importance in stem cell biology and development. Brain cell RNA-seq studies reveled Prmt1 expression in all major CNS cell types, including neurons, astrocytes, oligodendrocytes, and microglia, with little difference in expression levels among these cell types [13]. Recent reports have revealed the significance of PRMT1 in neural cells, particularly in proliferation, differentiation, and development. Furthermore, several reports suggest the involvement of PRMT1 in various CNS diseases, including neurodegenerative disorders, brain tumors and multiple sclerosis. These findings suggest that PRMT1 critically regulates development and physiological functions of the brain.
This minireview highlights the roles of PRMT1 in development and regulation of the mammalian CNS, focusing on each neural cell type (Fig. 2). In addition, roles of PRMT1 in disease contexts are discussed.
Section snippets
PRMT1 in neural stem cells
Systemic knockout of Prmt1 in murine embryos was made by inserting βgeo into the second intron of the murine Prmt1 gene [4]. X-Gal-stained Prmt1-positive cells first appeared in the neural plate of heterozygotes at E7.5, and the signal got stronger as it developed into the neural tube and the brain at E8.5–E9.5 [4], implying that PRMT1 is important for early neural development.
Based on early seminal studies, PRMT1 is recognized as an important epigenetic regulator, as it methylates histone H4
PRMT1 in astrocytes, oligodendrocytes, and microglia
As described in the previous section, Honda et al. revealed that PRMT1 knockdown in cultured NSCs suppressed GFAP expression, leading to inhibition of astrocyte differentiation [9]. Interestingly, our recent work demonstrated increases in GFAP-positive astrocytes and IBA-1-positive microglia in cortices following PRMT1 knockout in NSCs in vivo [19]. We also found that purified astrocytes from CKO embryos expressed similar level of GFAP with astrocytes from wildtype embryos, suggesting that
PRMT1 in neurons
An earlier study by Cimato et al. demonstrated that total type I arginine-methylated protein levels are increased by nerve-growth factor (NGF) treatment on PC12 cells and this modification is essential for NGF-induced neurite outgrowth [23]. These studies first implicated that arginine methylation by type I PRMTs is important for neurite outgrowth. Similarly, Prmt1 knockdown in a neuroblastoma cell line, Neuro2a, reportedly results in a low number of neurite-bearing cells under
PRMT1 in neurodegenerative diseases
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes motor neuron dysfunction, resulting in muscle weakness. One of the disease-causative mutations for this fatal disease was identified in fused in sarcoma (FUS) protein, which belongs to the FET (FUS/EWS/TAF15) family of RNA binding proteins. In addition, FUS is mutated in rare cases of frontotemporal dementia (FTD), a major neurodegenerative disease [31]. Recent reports suggest that loss of PRMT1 is associated with
PRMT1 in other CNS diseases
A number of studies have focused on PRMT1 in cancer development, as reviewed elsewhere [39], but its involvement in CNS tumors has not been well studied so far. Medulloblastoma, a tumor observed in the cerebellum, is the most common type of brain tumor in childhood. In general, PRMT1 leads to apoptosis by methylation of BCL-2 antagonist of cell death (BAD) protein [40]. A recent report indicated that this PRMT1-BAD axis could suppress tumor development by increasing tumor apoptosis and PRMT1
Future perspectives
We here overviewed the physiological and pathological roles of PRMT1 in the CNS (Fig. 2), but there remain many open questions. First, what are the key substrates of PRMT1 regulating CNS development and functions? To address this question, highly sensitive and specific methods are required to enrich methylated substrates in the CNS. To this end, a set of antibodies targeting ADMA, SDMA, and MMA were generated using synthetic methylated peptides with arginine-glycine-rich motifs, and were
Author contributions
MH wrote the original manuscript, and MH, AF, TN, and YK revised the manuscript. All authors approved submission of the manuscript.
Declaration of Competing Interest
The authors declare that they have no conflicts of interest with regard to the contents of this article.
Acknowledgements
This work was partially supported by JSPS KAKENHI Grant-in-Aid for Research Activity Start-Up (17H06730) to MH, JSPS KAKENHI Grant-in-Aid for Young Scientists (20K15913) to MH, Grant-in-Aid for Scientific Research (A) (17H01519) to AF, JSPS Leading Initiative for Excellent Young Researchers (LEADER) to YK, the Gifu University Yoshizaki Research Support Fund (YRSF) to MH, Inamori Foundation Research Grants to MH, and The Mitsubishi Foundation to AF. We thank Edanz Group (//en-author-services.edanzgroup.com/ac
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