PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination

Kim, Jun-Dal; Park, Kyung-eui; Ishida, Junji; Kako, Koichiro; Hamada, Juri; Kani, Shuichi; Takeuchi, Miki; Namiki, Kana; Fukui, Hajime; Fukuhara, Shigetomo; Hibi, Masahiko; Kobayashi, Makoto; Kanaho, Yasunori; Kasuya, Yoshitoshi; Mochizuki, Naoki; Fukamizu, Akiyoshi

doi:10.1126/sciadv.1500615

Cited by 49 publications

(61 citation statements)

References 52 publications

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“…Despite a previous study reporting deficits in motor coordination and performance of Prmt8 −/− mice (Kim et al . ), our data (Figure S2c and d) suggest that these mice do not perform significantly different in the water task as compared to wild‐type mice.…”

Section: Discussionmentioning

confidence: 50%

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Network‐based characterization of the synaptic proteome reveals that removal of epigenetic regulator Prmt8 restricts proteins associated with synaptic maturation

Lee

Goh

Sng

2017

Journal of Neurochemistry

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The brain adapts to dynamic environmental conditions by altering its epigenetic state, thereby influencing neuronal transcriptional programs. An example of an epigenetic modification is protein methylation, catalyzed by protein arginine methyltransferases (PRMT). One member, Prmt8, is selectively expressed in the central nervous system during a crucial phase of early development, but little else is known regarding its function. We hypothesize Prmt8 plays a role in synaptic maturation during development. To evaluate this, we used a proteome-wide approach to characterize the synaptic proteome of Prmt8 knockout versus wild-type mice. Through comparative network-based analyses, proteins and functional clusters related to neurite development were identified to be differentially regulated between the two genotypes. One interesting protein that was differentially regulated was tenascin-R (TNR). Chromatin immunoprecipitation demonstrated binding of PRMT8 to the tenascin-r (Tnr) promoter. TNR, a component of perineuronal nets, preserves structural integrity of synaptic connections within neuronal networks during the development of visual-somatosensory cortices. On closer inspection, Prmt8 removal increased net formation and decreased inhibitory parvalbumin-positive (PV+) puncta on pyramidal neurons, thereby hindering the maturation of circuits. Consequently, visual acuity of the knockout mice was reduced. Our results demonstrated Prmt8's involvement in synaptic maturation and its prospect as an epigenetic modulator of developmental neuroplasticity by regulating structural elements such as the perineuronal nets.

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Section: Discussionmentioning

confidence: 50%

“…Despite this, Prmt8 −/− mice developed normally and did not display any observable deficit, as previously described (Kim et al . ). However, since inhibition is crucial for the development of the visual cortex (Hensch et al .…”

Section: Resultsmentioning

confidence: 97%

Network‐based characterization of the synaptic proteome reveals that removal of epigenetic regulator Prmt8 restricts proteins associated with synaptic maturation

Lee

Goh

Sng

2017

Journal of Neurochemistry

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“…Although PAPOLB polyadenylation activity is most likely essential for spermatogenesis, we cannot rule out the possibility that Asp 114 of PAPOLB is involved in another yet unknown activity, as is the case for protein arginine methyltransferase 8 (PRMT8), in which Ser 120 is required for both arginine methylation and phosphatidylcholine hydrolysis activities [39]. At any rate, further studies, including the identification of the “true” target(s), are necessary to elucidate PAPOLB function.…”

Section: Discussionmentioning

confidence: 99%

Adenylation by testis-specific cytoplasmic poly(A) polymerase, PAPOLB/TPAP, is essential for spermatogenesis

Kashiwabara

Tsuruta

Okada

et al. 2016

Journal of Reproduction and Development

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The testis-specific cytoplasmic poly(A) polymerase PAPOLB/TPAP is essential for spermatogenesis. Although this enzyme is responsible for poly(A) tail extension of a subset of mRNAs in round spermatids, the stability and translational efficiency of these mRNAs are unaffected by the absence of PAPOLB. To clarify the functional importance of this enzyme’s adenylation activity, we produced PAPOLB-null mice expressing a polyadenylation-defective PAPOLB mutant (PAPOLBD114A), in which the catalytic Asp at residue 114 was mutated to Ala. Introducing PAPOLBD114A failed to rescue PAPOLB-null phenotypes, such as reduced expression of haploid-specific mRNAs, spermiogenesis arrest, and male infertility. These results suggest that PAPOLB regulates spermatogenesis through its adenylation activity.

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“…In this regard, recent work unexpectedly showed that PRMT8 has phospholipase function, which is attributed to its HKD motif (HxKxxxxDxxxxxxGG/S) that is distinct from the other PRMTs yet characteristic of phospholipase D enzymes. [108] PRMT1 has been found to exist as several isoforms, at least two of which are enzymatically inactive. [45a,109] Exact functions of these inactive PRMT1 isoforms remain to be determined.…”

Section: Summary and Perspectivementioning

confidence: 99%

Mechanisms and Inhibitors of Histone Arginine Methylation

Fulton

Brown

Zheng

2018

The Chemical Record

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Histone methylation plays an important regulatory role in chromatin restructuring and RNA transcription. Arginine methylation that is enzymatically catalyzed by the family of protein arginine methyltransferases (PRMTs) can either activate or repress gene expression depending on cellular contexts. Given the strong correlation of PRMTs with pathophysiology, great interest is seen in understanding molecular mechanisms of PRMTs in diseases and in developing potent PRMT inhibitors. Herein, we reviewed key research advances in the study of biochemical mechanisms of PRMT catalysis and their relevance to cell biology. We highlighted how a random binary, ordered ternary kinetic model for PRMT1 catalysis reconciles the literature reports and endorses a distributive mechanism that the enzyme active site utilizes for multiple turnovers of arginine methylation. We discussed the impacts of histone arginine methylation and its biochemical interplays with other key epigenetic marks. Challenges in developing small-molecule PRMT inhibitors were also discussed.

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PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination

Abstract: PRMT8 directly hydrolyzes phosphatidylcholine, which is important for brain functions.

Cited by 49 publications

References 52 publications

Network‐based characterization of the synaptic proteome reveals that removal of epigenetic regulator Prmt8 restricts proteins associated with synaptic maturation

Network‐based characterization of the synaptic proteome reveals that removal of epigenetic regulator Prmt8 restricts proteins associated with synaptic maturation

Adenylation by testis-specific cytoplasmic poly(A) polymerase, PAPOLB/TPAP, is essential for spermatogenesis

Mechanisms and Inhibitors of Histone Arginine Methylation

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