Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

Jordan, Philip W.; Karppinen, Jesse; Handel, Mary Ann

doi:10.1242/jcs.105015

Cited by 95 publications

(90 citation statements)

References 56 publications

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“…In Saccharomyces cerevisiae, APC/C AMA1 targets both cyclin B1 and the yeast PLK1 homolog Polo (Cdc5) to maintain appropriate prophase I timing (Okaz et al, 2012). Consistent with a previous recent study (Jordan et al, 2012) immunohistochemistry revealed chromatin-associated localization of PLK1 in control spermatocytes, which was similar in the few detectable FZR1Δ spermatocytes. Additionally, immunoblotting of D11 testis suggested that PLK1 protein was not prematurely increased in FZR1Δ animals (supplementary material Fig.…”

Section: Cyclin B1 Is Upregulated In Germ Cells Lacking Fzr1supporting

confidence: 92%

The APC/C activator FZR1 is essential for meiotic prophase I in mice

et al. 2014

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Fizzy-related 1 (FZR1) is an activator of the Anaphase promoting complex/cyclosome (APC/C) and an important regulator of the mitotic cell division cycle. Using a germ-cell-specific conditional knockout model we examined its role in entry into meiosis and early meiotic events in both sexes. Loss of APC/C FZR1 activity in the male germline led to both a mitotic and a meiotic testicular defect resulting in infertility due to the absence of mature spermatozoa. Spermatogonia in the prepubertal testes of such mice had abnormal proliferation and delayed entry into meiosis. Although early recombination events were initiated, male germ cells failed to progress beyond zygotene and underwent apoptosis. Loss of APC/C FZR1 activity was associated with raised cyclin B1 levels, suggesting that CDK1 may trigger apoptosis. By contrast, female FZR1Δ mice were subfertile, with premature onset of ovarian failure by 5 months of age. Germ cell loss occurred embryonically in the ovary, around the time of the zygotenepachytene transition, similar to that observed in males. In addition, the transition of primordial follicles into the growing follicle pool in the neonatal ovary was abnormal, such that the primordial follicles were prematurely depleted. We conclude that APC/C FZR1 is an essential regulator of spermatogonial proliferation and early meiotic prophase I in both male and female germ cells and is therefore important in establishing the reproductive health of adult male and female mammals. KEY WORDS: FZR1, Mouse, Meiosis, Spermatogenesis, Oogenesis, APC/C, CDH1 INTRODUCTIONDespite temporal differences in their meiotic programs, both sexes and indeed all eukaryotes, have a requirement for a prolonged prophase I to allow for homologous chromosome organization. In yeast, this is achieved through targeted proteolysis of M-phase promoting proteins by the Anaphase promoting complex/cyclosome (APC/C) complex, together with a meiosis specific coactivator protein, AMA1 (Cooper et al., 2000; Okaz et al., 2012). The mammalian meiotic program is punctuated by more complex 'stops' and 'starts' than those of lower eukaryotes, and the regulatory mechanisms behind these events -such as whether the meiotic role of the APC/C is conserved, has remained largely unexplored. In mammals, germ cell development encompasses a highly coordinated series of cell cycle changes. In the female, meiosis is initiated embryonically such that by birth oocytes are arrested at dictyate stage of prophase I within a primordial follicle (Adams and McLaren, 2002). Meiosis I is re-initiated at the time of ovulation but arrested once again at metaphase II until fertilization. By contrast, after a period of mitotic proliferation, after sex determination, embryonic male germ cells (gonocytes) enter quiescence. Postnatally they migrate to the basement membrane, re-enter the cell cycle and develop into undifferentiated spermatogonial cells. Some gonocytes establish the self-renewing stem cell population whereas others become differentiated spermatogonia that comple...

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Section: Cyclin B1 Is Upregulated In Germ Cells Lacking Fzr1supporting

confidence: 92%

The APC/C activator FZR1 is essential for meiotic prophase I in mice

et al. 2014

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“…We next examined whether the level of cAMP controls the disassembly and degradation of SYCP1 in oocytes. To assess the disassembly of the SYCP1 protein, we cultured ovaries (16.5 dpc) with MDL-12,330 and performed chromosome spreads and immunofluorescence staining as previously reported (Jordan et al, 2012). In this approach, linear SYCP1 staining indicated that the synaptonemal complex (SC) was integrated with SYCP1, whereas discontinuous or lack of SYCP1 staining indicated disassembly of SYCP1 from the SC (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies demonstrated that separation of the SC is essential for spermatocytes to enter the diplotene stage of meiosis in rodents (Tarsounas et al, 1999;Jordan et al, 2012). Here we show that the level of oocyte cAMP regulates the dissolution of SYCP1 from the SC.…”

Section: Discussionmentioning

confidence: 97%

Cyclic AMP in oocytes controls meiotic prophase I and primordial folliculogenesis in the perinatal mouse ovary

Wang

Teng

et al. 2015

Development

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In mammalian ovaries, a fixed population of primordial follicles forms during the perinatal stage and the oocytes contained within are arrested at the dictyate stage of meiotic prophase I. In the current study, we provide evidence that the level of cyclic AMP (cAMP) in oocytes regulates oocyte meiotic prophase I and primordial folliculogenesis in the perinatal mouse ovary. Our results show that the early meiotic development of oocytes is closely correlated with increased levels of intra-oocyte cAMP. Inhibiting cAMP synthesis in fetal ovaries delayed oocyte meiotic progression and inhibited the disassembly and degradation of synaptonemal complex protein 1. In addition, inhibiting cAMP synthesis in in vitro cultured fetal ovaries prevented primordial follicle formation. Finally, using an in situ oocyte chromosome analysis approach, we found that the dictyate arrest of oocytes is essential for primordial follicle formation under physiological conditions. Taken together, these results suggest a role for cAMP in early meiotic development and primordial follicle formation in the mouse ovary.

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“…Thus, the inhibition of cell cycle progression is caused by the inhibition of the kinase activity of the PLKs. In fact, Jordan et al have discovered the great importance of PLKs in synaptonemal complex disassembly in mouse spermatocytes by brief in vitro culture of spermatocytes (12). Recently, Cdc5, an ortholog of the PLKs, was found to be a central regulator of meiosis I in yeast (59).…”

Section: Discussionmentioning

confidence: 99%

Systematic Analysis of the Phosphoproteome and Kinase-substrate Networks in the Mouse Testis

Lin

Liu

Wang

et al. 2014

Molecular & Cellular Proteomics

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Spermatogenesis is a complex process closely associated with the phosphorylation-orchestrated cell cycle. Elucidating the phosphorylation-based regulations should advance our understanding of the underlying molecular mechanisms. Here we present an integrative study of phosphorylation events in the testis. Large-scale phosphoproteome profiling in the adult mouse testis identified 17,829 phosphorylation sites in 3955 phosphoproteins. Although only approximately half of the phosphorylation sites enriched by IMAC were also captured by TiO 2 , both the phosphoprotein data sets identified by the two methods significantly enriched the functional annotation of spermatogenesis. Thus, the phosphoproteome profiled in this study is a highly useful snapshot of the phosphorylation events in spermatogenesis. To further understand phosphoregulation in the testis, the site-specific kinasesubstrate relations were computationally predicted for reconstructing kinase-substrate phosphorylation networks. A core sub-kinase-substrate phosphorylation networks among the spermatogenesis-related proteins was retrieved and analyzed to explore the phosphoregulation during spermatogenesis. Moreover, network-based analyses demonstrated that a number of protein kinases such as MAPKs, CDK2, and CDC2 with statistically more sitespecific kinase-substrate relations might have significantly higher activities and play an essential role in spermatogenesis, and the predictions were consistent with previous studies on the regulatory roles of these kinases. In particular, the analyses proposed that the activities of POLO-like kinases (PLKs) might be dramatically higher, while the prediction was experimentally validated by detecting and comparing the phosphorylation levels of pT210, an indicator of PLK1 activation, in testis and other tissues. Further experiments showed that the inhibition of POLO-like kinases decreases cell proliferation by inducing G2/M cell cycle arrest. Taken together, this systematic study provides a global landscape of phosphoregulation in the testis, and should prove to be of value in future studies of spermatogenesis. Molecular & Cellular Proteomics 13:

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Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

Cited by 95 publications

References 56 publications

The APC/C activator FZR1 is essential for meiotic prophase I in mice

The APC/C activator FZR1 is essential for meiotic prophase I in mice

Cyclic AMP in oocytes controls meiotic prophase I and primordial folliculogenesis in the perinatal mouse ovary

Systematic Analysis of the Phosphoproteome and Kinase-substrate Networks in the Mouse Testis

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