Mice Lacking the USP2 Deubiquitinating Enzyme Have Severe Male Subfertility Associated with Defects in Fertilization and Sperm Motility

Bédard, Nathalie; Yang, Yaoming; Gregory, Mary; Cyr, Daniel G.; Suzuki, J; Yu, Xuen; Chian, Ri‐Cheng; Hermo, Louis; O’Flaherty, Cristián; Smith, Charles E.; Clarke, Hugh J.; Wing, Simon S.

doi:10.1095/biolreprod.110.088542

Cited by 62 publications

(54 citation statements)

References 59 publications

(62 reference statements)

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“…According to the detailed phenotypic analysis provided by Deltagen and our own observations, homozygote KO mice are viable and were born at Mendelian ratio, indicating that Usp2-KO animals do not die prematurely during development. Similarly to what was described previously with another Usp2-KO model, the fertility of male KO mice was strongly reduced (5). The mice did not show any growth defect or any other obvious morphological changes, as assessed by the mouse phenotyping platform of Deltagen.…”

Section: Resultssupporting

confidence: 72%

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

Pouly

Debonneville

Ruffieux-Daidié

et al. 2013

American Journal of Physiology-Renal Physiology

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Section: Resultssupporting

confidence: 72%

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

Pouly

Debonneville

Ruffieux-Daidié

et al. 2013

American Journal of Physiology-Renal Physiology

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“…In addition, at least Mtap2, Eif4g3, Usp2, Mtap7, Ace, and Tex14 are known to play a role in male fertility (29)(30)(31)(32)(33)(34), and overexpression of Spata17 and Rpgr leads to male infertility (35,36). Therefore, the infertility in the Mrg15 cKO mice could be secondary to alterations in the levels of these proteins.…”

Section: Spermatogenesis In Mrg15mentioning

confidence: 99%

MRG15 is required for pre-mRNA splicing and spermatogenesis

Iwamori

Tominaga

Sato

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Splicing can be epigenetically regulated and involved in cellular differentiation in somatic cells, but the interplay of epigenetic factors and the splicing machinery during spermatogenesis remains unclear. To study these interactions in vivo, we generated a germline deletion of MORF-related gene on chromosome 15 (MRG15), a multifunctional chromatin organizer that binds to methylated histone H3 lysine 36 (H3K36) in introns of transcriptionally active genes and has been implicated in regulation of histone acetylation, homology-directed DNA repair, and alternative splicing in somatic cells. Conditional KO (cKO) males lacking MRG15 in the germline are sterile secondary to spermatogenic arrest at the round spermatid stage. There were no significant alterations in meiotic division and histone acetylation. Specific mRNA sequences disappeared from 66 germ cell-expressed genes in the absence of MRG15, and specific intronic sequences were retained in mRNAs of 4 genes in the MRG15 cKO testes. In particular, introns were retained in mRNAs encoding the transition proteins that replace histones during sperm chromatin condensation. In round spermatids, MRG15 colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites between the exons and single intron of transition nuclear protein 2 (Tnp2). Thus, our results reveal that MRG15 is essential for premRNA splicing during spermatogenesis and that epigenetic regulation of pre-mRNA splicing by histone modification could be useful to understand not only spermatogenesis but also, epigenetic disorders underlying male infertile patients.infertility | fertility defects | splicing defects | epigenetics | spermiogenesis S permatogenesis is a complex process involving several biological events and dramatic changes of chromatin structure. Male germ cells undergo stem cell self-renewal, mitotic divisions in spermatogonial proliferation, genomic rearrangement by meiotic homologous recombination at the spermatocyte stage, and morphological changes of round spermatids into elongated spermatids to form mature spermatozoa (1-3). During spermiogenesis, nucleosomal histone proteins are replaced with transition nuclear proteins (TNPs) and subsequently, protamines, the major nucleosomal proteins in spermatozoa. Moreover, epigenetic modifications, such as histone methylation, dramatically change throughout spermatogenesis (3, 4).Pre-mRNA splicing generates protein diversity and is involved in the regulation of cellular differentiation (5, 6). Recent advances have shown that histone modifications regulate alternative splicing through recruitment of splicing regulators via chromatin binding proteins, such as MORF-related gene on chromosome 15 (MRG15) (7). Histone H3 lysine 36 (H3K36) is methylated proximal to tissuespecific splicing regions (8-12). MRG15 specifically recognizes the methylated H3K36 and recruits polypyrimidine tract binding protein (PTB) at intronic splicing silencer elements near an exon to suppress exon insertions into mRNA (7). MRG15 is also a component of histone acetyltransfe...

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“…Fusion and differentiation are stimulated by overexpression of USP2a whereas overexpression of USP2b inhibits these processes. However, it appears that USP2 is not essential for myogenesis as skeletal muscle appears grossly normal in mice lacking USP2, albeit both isoforms ( (Bedard et al, 2011) and data not published).…”

Section: Other Deubiquitinases and Skeletal Musclementioning

confidence: 99%

Deubiquitinases in skeletal muscle atrophy

Wing¹

2013

The International Journal of Biochemistry & Cell Biology

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The ubiquitin proteasome system plays a critical role in skeletal muscle atrophy. A large body of research has revealed that many ubiquitin ligases are induced and play an important role in mediating the wasting. However, relatively little is known about the roles of deubiquitinases in this process. Although it might be expected that deubiquitinases would be downregulated in atrophying muscles to promote ubiquitination and degradation of muscle proteins, this has not to date been demonstrated. Instead several deubiquitinases are induced in atrophying muscle, in particular USP19 and USP14. USP19, USP2 and A20 are also implicated in myogenesis. USP19 has been most studied to date. Its expression is increased in both systemic and disuse forms of atrophy and can be regulated through a p38 MAP kinase signaling pathway. In cultured muscle cells, it decreases the expression of myofibrillar proteins by apparently suppressing their transcription indicating that the ubiquitin proteasome system may be activated in skeletal muscle to not only increase protein degradation, but also to suppress protein synthesis. Deubiquitinases may be upregulated in atrophy in order to maintain the pool of free ubiquitin required for the increased overall conjugation and degradation of muscle proteins as well as to regulate the stability and function of proteins that are essential in mediating the wasting. Although deubiquitinases are not well studied, these early insights indicate that some of these enzymes play important roles and may be therapeutic targets for the prevention and treatment of muscle atrophy. KeywordsUbiquitin; Skeletal muscle; Myofibrillar proteins; Deubiquitination; Cachexia Increased ubiquitination of muscle proteins in atrophic conditionsThe first observations of activation of the ubiquitin-proteasome system (UPS) in conditions of muscle wasting were reported approximately twenty years ago (Haas and Riley, 1988;Medina et al., 1991). Amongst these findings were key observations that the increases in rates of proteolysis observed upon fasting or denervation -prototypic conditions of muscle wasting due to systemic regulatory factors or loss of neural activity respectively -were largely due to an ATP dependent mechanism (Furuno et al., 1990;Wing and Goldberg, 1993). Importantly, expression of ubiquitin and ubiquitinated proteins increased in skeletal muscle in parallel with these increases in rates of ATP dependent proteolysis (Medina et al.,

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Mice Lacking the USP2 Deubiquitinating Enzyme Have Severe Male Subfertility Associated with Defects in Fertilization and Sperm Motility

Cited by 62 publications

References 59 publications

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

MRG15 is required for pre-mRNA splicing and spermatogenesis

Deubiquitinases in skeletal muscle atrophy

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