Impairment of Pachytene Spermatogenesis in<i>Dmrt7</i>Deficient Mice, Possibly Causing Meiotic Arrest

Date, Shiori; Nozawa, Osamu; Inoue, Hiroaki; Hidema, Shizu; Nishimori, Katsuhiko

doi:10.1271/bbb.120024

Cited by 13 publications

(14 citation statements)

References 39 publications

(52 reference statements)

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“…These indicated that the antibodies induced meiotic arrest at the stages when the corresponding protease began to be produced. There are some studies reporting that meiotic arrest could lead to germ cell apoptosis [23,60,61]. Therefore, we conclude that the Prss42/Tessp-2 and Prss43/Tessp-3 antibodies induced meiotic arrest in primary and secondary spermatocytes, respectively, which could result in their apoptosis.…”

Section: The Prss42/tessp-2 and Prss43/tessp-3 Proteases Are Involvedmentioning

confidence: 60%

Three Testis-Specific Paralogous Serine Proteases Play Different Roles in Murine Spermatogenesis and Are Involved in Germ Cell Survival During Meiosis1

Yoneda

Takahashi

Matsui

et al. 2013

Biology of Reproduction

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Spermatogenesis is a complex process that generates spermatozoa; its molecular mechanisms are not completely understood. Here we focused on the functions of three testis-specific serine proteases: Prss42/Tessp-2, Prss43/Tessp-3, and Prss44/Tessp-4. These protease genes, which constitute a gene cluster on chromosome 9F2-F3, were presumed to be paralogs and were expressed only in the testis. By investigating their mRNA distribution, we found that all three genes were expressed in primary and secondary spermatocytes. However, interestingly, the translated proteins were produced at different locations. Prss42/Tessp-2 was found in the membranes and cytoplasm of secondary spermatocytes and spermatids, whereas Prss43/Tessp-3 was present only in the membranes of spermatocytes and spermatids. Prss44/Tessp-4 was detected in the cytoplasm of spermatocytes and spermatids. To assess the roles of these proteases in spermatogenesis, we used organ culture of mouse testis fragments. Adding antibodies against Prss42/Tessp-2 and Prss43/Tessp-3 resulted in meiotic arrest at the stage when each protease was beginning to be translated. Furthermore, the number of apoptotic cells dramatically increased after the addition of these antibodies. These results strongly suggest that the three paralogous Prss/Tessp proteases play different roles in spermatogenesis and that Prss42/Tessp-2 and Prss43/Tessp-3 are required for germ cell survival during meiosis.

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Section: The Prss42/tessp-2 and Prss43/tessp-3 Proteases Are Involvedmentioning

confidence: 60%

Three Testis-Specific Paralogous Serine Proteases Play Different Roles in Murine Spermatogenesis and Are Involved in Germ Cell Survival During Meiosis1

Yoneda

Takahashi

Matsui

et al. 2013

Biology of Reproduction

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“…Intriguingly, mice lacking Mybl1 show defective spermatogenesis, which resembles the phenotype of Cdk2- or cyclin E-deficient mice [28,29]. Dmrtc2 is also essential for male spermatogenesis, and Dmrtc2-deficient mice show a similar testicular phenotype with spermatogenic arrest at the pachytene stage [30,31]. Importantly, our Scansite 3.0 analyses of the testicular interactome identified both Mybl1 and Dmrtc2 as predicted Cdk phosphorylation substrates (S2 Table).…”

Section: Resultsmentioning

confidence: 95%

“…Dmrtc2 is an essential regulator of spermatogenesis, and mice lacking this protein present impairment in spermatogenesis characterized by developmental arrest at the pachytene stage [30,31]. However, the molecular function of Dmrtc2 in spermatogenesis is not yet well understood.…”

Section: Resultsmentioning

confidence: 99%

“…Dmrtc2 represents another critical protein implicated in mouse spermatogenesis, and spermatocytes lacking Dmrtc2 exhibit pachytene arrest, similar to testicular phenotype seen in Cdk2- or cyclin E-deficient animals [30,31]. We found that, like Mybl1, Dmrtc2 also represents a direct cyclin E-Cdk2 phosphorylation target, and that the levels of Dmrtc2 are reduced in the testes of mice lacking Cdk2 or cyclin E. Collectively, these results suggest that cyclin E-Cdk2 represents a crucial upstream regulator of the transcriptional cascade in the male germline, by acting through Mybl1 and Dmrtc2.…”

Section: Discussionmentioning

confidence: 99%

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Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo

et al. 2016

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E-type cyclins (cyclins E1 and E2) are components of the cell cycle machinery that has been conserved from yeast to humans. The major function of E-type cyclins is to drive cell division. It is unknown whether in addition to their ‘core’ cell cycle functions, E-type cyclins also perform unique tissue-specific roles. Here, we applied high-throughput mass spectrometric analyses of mouse organs to define the repertoire of cyclin E protein partners in vivo. We found that cyclin E interacts with distinct sets of proteins in different compartments. These cyclin E interactors are highly enriched for phosphorylation targets of cyclin E and its catalytic partner, the cyclin-dependent kinase 2 (Cdk2). Among cyclin E interactors we identified several novel tissue-specific substrates of cyclin E-Cdk2 kinase. In proliferating compartments, cyclin E-Cdk2 phosphorylates Lin proteins within the DREAM complex. In the testes, cyclin E-Cdk2 phosphorylates Mybl1 and Dmrtc2, two meiotic transcription factors that represent key regulators of spermatogenesis. In embryonic and adult brains cyclin E interacts with proteins involved in neurogenesis, while in adult brains also with proteins regulating microtubule-based processes and microtubule cytoskeleton. We also used quantitative proteomics to demonstrate re-wiring of the cyclin E interactome upon ablation of Cdk2. This approach can be used to study how protein interactome changes during development or in any pathological state such as aging or cancer.

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“…Each reaction was performed in triplicate. The values were normalized to the expression of the gene encoding ribosomal protein, large, P0 (Rplp0) (also named Arbp, acidic ribosomal phosphoprotein P0) as an internal control as previously reported (15)(16)(17)(18)(19). Statistical analyses were performed with two-way ANOVA followed by Tukey's comparisons test (GraphPad Prism software) as discussed below in the Statistical Analysis section.…”

Section: Quantitative Real-time Pcr From Paraformaldehydefixed Parafmentioning

confidence: 99%

Prolonged Oral Administration of a Pan-Retinoic Acid Receptor Antagonist Inhibits Spermatogenesis in Mice With a Rapid Recovery and Changes in the Expression of Influx and Efflux Transporters

2016

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We have previously shown that oral administration of a pan-retinoic acid receptor antagonist in mice daily at 2.5 mg/kg for 4 weeks reversibly inhibited spermatogenesis, with no detectable side effects. To elucidate the lowest dose and the longest dosing regimen that inhibits spermatogenesis but results in complete restoration of fertility upon cessation of administration of the drug, we examined the effects of daily doses as low as 1.0 mg/kg with dosing periods of 4, 8, and 16 weeks. We observed 100% sterility in all regimens, with restoration of fertility upon cessation of the drug treatment even for as long as 16 weeks. There was no change in testosterone levels in these males and the progeny examined from 2 of the recovered males were healthy and fertile, with normal testicular weight and testicular histology. Strikingly, a more rapid recovery, as assessed by mating studies, was observed at the lower dose and longer dosing periods. Insight into possible mechanisms underlying this rapid recovery was obtained at 2 levels. First, histological examination revealed that spermatogenesis was not as severely disrupted at the lower dose and with the longer treatment regimens. Second, gene expression analysis revealed that the more rapid recovery may involve the interplay of ATP-binding cassette efflux and solute carrier influx transporters in the testes.

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Impairment of Pachytene Spermatogenesis inDmrt7Deficient Mice, Possibly Causing Meiotic Arrest

Cited by 13 publications

References 39 publications

Three Testis-Specific Paralogous Serine Proteases Play Different Roles in Murine Spermatogenesis and Are Involved in Germ Cell Survival During Meiosis1

Three Testis-Specific Paralogous Serine Proteases Play Different Roles in Murine Spermatogenesis and Are Involved in Germ Cell Survival During Meiosis1

Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo

Prolonged Oral Administration of a Pan-Retinoic Acid Receptor Antagonist Inhibits Spermatogenesis in Mice With a Rapid Recovery and Changes in the Expression of Influx and Efflux Transporters

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