Mammalian E-type Cyclins Control Chromosome Pairing, Telomere Stability and CDK2 Localization in Male Meiosis

Martinerie, Lætitia; Manterola, Marcia; Chung, Sydney S.C.; Panigrahi, Sunil K.; Weisbach, Melissa M.; Vasil’eva, A. A.; Geng, Yan; Sicinski, Peter; Wolgemuth, Debra J.

doi:10.1371/journal.pgen.1004165

Cited by 43 publications

(77 citation statements)

References 45 publications

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“…It has been reported that E-type cyclins (E1 and E2) also form complexes with Cdk2 in mouse spermatocytes, and the knockout mice for Ccne1 and Ccne2 partially mimic the phenotypes seen in Cdk2 −/− spermatocytes, suggesting the involvement of canonical cyclins in the activation of Cdk2 during meiosis (35,36).…”

Section: Discussionmentioning

confidence: 99%

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

Bayazit

Liu

et al. 2016

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

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Telomere attachment to the nuclear envelope (NE) is a prerequisite for chromosome movement during meiotic prophase I that is required for pairing of homologous chromosomes, synapsis, and homologous recombination. Here we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is specifically localized to telomeres in prophase I male and female germ cells in mice, and plays an essential role in the telomere-NE attachment. Deletion of Spdya in mice disrupts telomere-NE attachment, and this impairs homologous pairing and synapsis and leads to zygotene arrest in male and female germ cells. In addition, we have identified a telomere localization domain on Speedy A covering the distal N terminus and the Cdk2-binding Ringo domain, and this domain is essential for the localization of Speedy A to telomeres. Furthermore, we found that the binding of Cdk2 to Speedy A is indispensable for Cdk2's localization on telomeres, suggesting that Speedy A and Cdk2 might be the initial components that are recruited to the NE for forming the meiotic telomere complex. However, Speedy A-Cdk2-mediated telomere-NE attachment is independent of Cdk2 activation. Our results thus indicate that Speedy A and Cdk2 might mediate the initial telomere-NE attachment for the efficient assembly of the telomere complex that is essential for meiotic prophase I progression. meiosis | telomere | Speedy A | Cdk2 | germ cells

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Section: Discussionmentioning

confidence: 99%

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

Bayazit

Liu

et al. 2016

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

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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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“…In contrast to their overlapping expression in somatic cells, we previously reported that E-type cyclins exhibit distinct patterns of expression in the germ line, notably in meiotic spermatocytes rather than in mitotic spermatogonia (Martinerie et al 2014). Cyclin E1 expression is restricted to non-proliferating Sertoli cells and mid-pachytene to diplotene spermatocytes, where it is specifically localized along the axial element of the sex chromosomes.…”

Section: Introductionmentioning

confidence: 89%

“…Indeed, using constitutive and conditional knockout mice lines, we observed that cyclin E2-deficient ( E1+/+E2−/− ) males exhibited reduced fertility (Geng et al 2003; Martinerie et al 2014) resulting from meiotic defects in homologue pairing, synapsis and DNA repair (Martinerie et al 2014). The relevance of both E-type cyclins for male meiosis is also underscored by our observations that the additional loss of one E1 allele ( E1+/−E2−/− ) resulted in sterility, with severely disrupted spermatogenesis and enhanced meiotic defects (Martinerie et al 2014). The complete absence of E-type cyclins in the male germ line resulted in a meiotic catastrophe, with most spermatocytes arrested at zygotene and early pachytene-like stages.…”

Section: Introductionmentioning

confidence: 99%

E-type cyclins modulate telomere integrity in mammalian male meiosis

2015

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We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele (E1+/−E2−/−) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the Shelterin-complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres, and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of Shelterin-complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.

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Mammalian E-type Cyclins Control Chromosome Pairing, Telomere Stability and CDK2 Localization in Male Meiosis

Cited by 43 publications

References 45 publications

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

Speedy A–Cdk2 binding mediates initial telomere–nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation

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

E-type cyclins modulate telomere integrity in mammalian male meiosis

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