Severe Hypomyelination and Developmental Defects Are Caused in Mice Lacking Protein Arginine Methyltransferase 1 (PRMT1) in the Central Nervous System

Abstract

Protein arginine methyltransferase 1 (PRMT1) is involved in cell proliferation, DNA damage response, and transcriptional regulation. Although PRMT1 is extensively expressed in the CNS at embryonic and perinatal stages, the physiological role of PRMT1 has been poorly understood. Here, to investigate the primary function of PRMT1 in the CNS, we generated CNSspecific PRMT1 knock-out mice by the Cre-loxP system. These mice exhibited postnatal growth retardation with tremors, and most of them died within 2 weeks after birth. Brain histological analyses revealed prominent cell reduction in the white matter tracts of the mutant mice. Furthermore, ultrastructural analysis demonstrated that myelin sheath was almost completely ablated in the CNS of these animals. In agreement with hypomyelination, we also observed that most major myelin proteins including myelin basic protein (MBP), 2,3-cyclic-nucleotide 3-phosphodiesterase (CNPase), and myelin-associated glycoprotein (MAG) were dramatically decreased, although neuronal and astrocytic markers were preserved in the brain of CNS-specific PRMT1 knock-out mice. These animals had a reduced number of OLIG2؉ oligodendrocyte lineage cells in the white matter.We found that expressions of transcription factors essential for oligodendrocyte specification and further maturation were significantly suppressed in the brain of the mutant mice. Our findings provide evidence that PRMT1 is required for CNS development, especially for oligodendrocyte maturation processes.CNS development is achieved by proliferation of progenitor cells followed by the transition from a proliferative state to differentiation. This process is considered to be tightly regulated at multiple levels such as gene transcription, translation, and protein modification. In the oligodendrocyte lineage, transcription factors are known to determine cell fate and timing of differentiation by inducing the target genes that are critical for myelination (1-3). Moreover, emerging evidence suggests that post-translational modification of proteins is one of the important determinants for oligodendrocyte lineage progression (4). For example, phosphorylation of retinoblastoma protein by AMP-activated protein kinase is essential for cell cycle progression in neural stem cells (NSCs) 2 and their differentiation into cell types including neurons and oligodendrocytes (5). On the other hand, a histone lysine deacetylase, SIRT1, has a role in limiting the expansion of oligodendrocyte precursor cells (OPCs) (6). However, there is no in vivo evidence for the involvement of methylation enzymes in oligodendrocyte development and myelination.Protein arginine methylation is now widely accepted as one of the major post-translational modifications observed in both histone and non-histone proteins. Protein arginine methyltransferase (PRMT) 1, one of the type I PRMTs that catalyze monomethylation and asymmetric dimethylation of proteins, regulates transcription, cell death, DNA damage responses, and signal transduction as reviewed elsewhere (7). I...

Asymmetric Arginine Dimethylation Modulates Mitochondrial Energy Metabolism and Homeostasis in Caenorhabditis elegans

“…In contrast, levels of symmetric dimethylarginine (SDMA) were increased in light but not heavy mitochondrial fractions (Fig. 2B, right), which is partially consistent with previous observations in mouse models (24,28). Taken together, these results indicate that PRMT-1 serves as the major enzyme catalyzing asymmetric arginine dimethylation in mitochondria, and the loss of PRMT-1 alters the dynamics of SDMA formation especially in the light mitochondrial fraction.…”

“…ADMA or SDMA was quantified using a Shimadzu Nexera ultrahigh-pressure liquid chromatography system coupled to an LCMS-8050 triple-quadrupole mass spectrometer (Shimadzu, Kyoto, Japan) as described previously (28). LC separation was performed on a SeQuant ZIC-HILIC column (2.1 by 150 mm; Merck KGaA, Darmstadt, Germany) with a SeQuant ZIC-HILIC guard fitting apparatus (1.0 by 14 mm; Merck KGaA) at 40°C.…”

Emerging Role for Methylation in Multiple Sclerosis: Beyond DNA

“…PRMT5 promotes stem cell renewal and is essential during ontogeny, including a requirement for PRMT5 in neuronal stem cells for murine brain development [89]. Additionally, severe hypomyelination is observed in CNS-specific Prmt1 -deficient mice [90], and PRMT5 deficiency in oligodendrocyte progenitor cells (OPCs) leads to upregulated expression of Inhibitors of Differentiation Id2 and Id4 , as well as an immature gene expression profile, suggesting PRMT5 is required for proper OPC differentiation into mature oligodendrocytes [91]. Although complete PRMT5 deficiency is incompatible with brain development, its requirements in the adult brain are less well defined and excess SDM is associated with brain pathology.…”

Arginine Methylation by PRMT1 Regulates Muscle Stem Cell Fate

“…In the past decade, the emergence of interest for arginine methylation roles has led to in vivo studies using mouse models. Depletion of the major type I (PRMT1) in mice leads to embryonic lethality (6, 7), and more recently the conditional removal of PRMT1 using Nestin-Cre has been shown to implicate asymmetrical arginine methylation in the process of myelination (8). PRMT2-null mice were shown to be hypophagic and lean, as STAT3 methylation is lost (9).…”