Mouse Pachytene Checkpoint 2 (Trip13) Is Required for Completing Meiotic Recombination but Not Synapsis

Li, Xin Chenglin; Schimenti, John C.

doi:10.1371/journal.pgen.0030130

Cited by 204 publications

(197 citation statements)

References 68 publications

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“…This hypothesis is supported by studies showing that in mice lacking proteins required to complete meiotic recombination and DNA repair, such as ATM, DMC1, Trip13 and Msh5, oocytes undergo apoptosis before diplotene arrest (Barlow et al 1998, Pittman et al 1998, Li & Schimenti 2007, Ene et al 2013. Our studies suggest that BMF is also involved in the elimination of germ cells during the early stages of meiosis; whether or not this involves the elimination of germ cells with meiotic defects is not known.…”

Section: Discussionsupporting

confidence: 63%

BCL2-modifying factor promotes germ cell loss during murine oogenesis

Vaithiyanathan¹,

Liew²,

Zerafa³

et al. 2016

Reproduction

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Apoptosis plays a prominent role during ovarian development by eliminating large numbers of germ cells from the female germ line. However, the precise mechanisms and regulatory proteins involved in germ cell death are yet to be determined. In this study, we characterised the role of the pro-apoptotic BH3-only protein, BCL2-modifying factor (BMF), in germ cell apoptosis in embryonic and neonatal mouse ovaries. BMF protein was immunohistochemically localised to germ cells at embryonic days 15.5 (E15.5) and E17.5 and postnatal day 1 (PN1), coincident with entry into the meiotic prophase, but was undetectable at E13.5, and only present at low levels at PN3 and PN5. Consistent with this expression pattern, loss of BMF in female mice was associated with a decrease in apoptosis at E15.5 and E17.5. Furthermore, increased numbers of germ cells were found in ovaries from Bmf −/− mice compared with WT animals at E15.5 and PN1. However, germ cell numbers were comparable between Bmf −/− and WT ovaries at PN3, PN5 and PN10. Collectively, these data indicate that BMF mediates foetal oocyte loss and its action limits the maximal number of germ cells attained in the developing ovary, but does not influence the number of primordial follicles initially established in ovarian reserve.

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Section: Discussionsupporting

confidence: 63%

BCL2-modifying factor promotes germ cell loss during murine oogenesis

Vaithiyanathan¹,

Liew²,

Zerafa³

et al. 2016

Reproduction

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“…Asynapsis is a common phenotype that can be caused by a variety of defects including mutations in genes involved in early recombination events or AE/SC structure, and an increasing number of studies have documented a close association between meiotic axis (AE/LE and/or SC) structure and crossover control (Zhang et al 2006;Golubovskaya et al 2006;Kleckner 2006;Li and Schimenti 2007;Börner et al 2008;Tsai et al 2008;Brar et al 2009;Joshi et al 2009;Zanders and Alani 2009;Wang et al 2010;Wood et al 2010;Kim et al 2010;Roig et al 2010;Daniel et al 2011). Our results show that meiotic chromosome axis structure, synapsis, and crossover control are all closely linked in plants as well.…”

Section: Asynapsis and Recombinationsupporting

confidence: 56%

Altered distribution of MLH1 foci is associated with changes in cohesins and chromosome axis compaction in an asynaptic mutant of tomato

2012

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In most multicellular eukaryotes, synapsis [synaptonemal complex (SC) formation] between pairs of homologous chromosomes during prophase I of meiosis is closely linked with crossing over. Asynaptic mutants in plants have reduced synapsis and increased univalent frequency, often resulting in genetically unbalanced gametes and reduced fertility. Surprisingly, some asynaptic mutants (like as1 in tomato) have wild-type or increased levels of crossing over. To investigate, we examined SC spreads from as1/as1 microsporocytes using both light and electron microscopic immunolocalization. We observed increased numbers of MLH1 foci (a crossover marker) per unit length of SC in as1 mutants compared to wild-type. These changes are associated with reduced levels of detectable cohesin proteins in the axial and lateral elements (AE/LEs) of SCs, and the AE/LEs of as1 mutants are also significantly longer than those of wild-type or another asynaptic mutant. These results indicate that chromosome axis structure, synapsis, and crossover control are all closely linked in plants.

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“…In some mutant mice (e.g., in Dmc1 À/À and Trip13 À/À mice), DSB repair defects are considered to be the likely primary cause of meiocyte apoptosis (Pittman et al 1998;Di Giacomo et al 2005;Li and Schimenti 2007;Burgoyne et al 2009;Roig et al 2010). In fact, DSB repair defects may trigger meiocyte elimination during prophase in Trip13 À/À cells in the absence of major SC formation defects (Li and Schimenti 2007;Roig et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, DSB repair defects may trigger meiocyte elimination during prophase in Trip13 À/À cells in the absence of major SC formation defects (Li and Schimenti 2007;Roig et al 2010). Nevertheless, DSB repair defects are unlikely to be the only lesions that are monitored by meiotic surveillance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms

Wojtasz¹,

Cloutier²,

Baumann³

et al. 2012

Genes Dev.

142

162

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Meiotic crossover formation involves the repair of programmed DNA double-strand breaks (DSBs) and synaptonemal complex (SC) formation. Completion of these processes must precede the meiotic divisions in order to avoid chromosome abnormalities in gametes. Enduring key questions in meiosis have been how meiotic progression and crossover formation are coordinated, whether inappropriate asynapsis is monitored, and whether asynapsis elicits prophase arrest via mechanisms that are distinct from the surveillance of unrepaired DNA DSBs. We disrupted the meiosis-specific mouse HORMAD2 (Hop1, Rev7, and Mad2 domain 2) protein, which preferentially associates with unsynapsed chromosome axes. We show that HORMAD2 is required for the accumulation of the checkpoint kinase ATR along unsynapsed axes, but not at DNA DSBs or on DNA DSBassociated chromatin loops. Consistent with the hypothesis that ATR activity on chromatin plays important roles in the quality control of meiotic prophase, HORMAD2 is required for the elimination of the asynaptic Spo11 -/-, but not the asynaptic and DSB repair-defective Dmc1 -/-oocytes. Our observations strongly suggest that HORMAD2-dependent recruitment of ATR to unsynapsed chromosome axes constitutes a mechanism for the surveillance of asynapsis. Thus, we provide convincing evidence for the existence of a distinct asynapsis surveillance mechanism that safeguards the ploidy of the mammalian germline.[Keywords: asynapsis surveillance; meiotic prophase checkpoint; ATR; HORMA domain; meiosis; aneuploidy] Supplemental material is available for this article. Received January 30, 2012; revised version accepted March 19, 2012. Orderly chromosome segregation during the first meiotic division requires that homologous maternal and paternal chromosomes (called homologs) become physically linked, thereby forming so-called bivalents during the first meiotic prophase (Page and Hawley 2003). In most organisms, including mammals, meiotic recombination generates reciprocal exchanges, called crossovers (COs), between homologous DNA sequences. Interhomolog COs and sister chromatid cohesion together form the basis of the physical linkages, called chiasmata, that connect pairs of homologs during the first meiotic metaphase. Therefore, at least one CO must form between each pair of homologs to ensure correct segregation during the first meiotic division.CO formation requires that homologs find each other. To achieve this, double-strand breaks (DSBs) are actively introduced into the genome at the beginning of prophase by the SPO11 enzyme (Keeney et al. 1997;Baudat et al. 2000;Romanienko and Camerini-Otero 2000). This is followed by the resection of DSB ends, which creates 39 ssDNA overhangs (Neale et al. 2005). The RAD51 and DMC1 recombinases bind single-stranded DSB ends and assist homology search through promoting strand invasion of resected DSB ends into homologous DNA sequences (Baudat and de Massy 2007). Several DSB ends work in parallel on each pair of homologs to ensure alignment along the full lengths of homolo...

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Mouse Pachytene Checkpoint 2 (Trip13) Is Required for Completing Meiotic Recombination but Not Synapsis

Cited by 204 publications

References 68 publications

BCL2-modifying factor promotes germ cell loss during murine oogenesis

BCL2-modifying factor promotes germ cell loss during murine oogenesis

Altered distribution of MLH1 foci is associated with changes in cohesins and chromosome axis compaction in an asynaptic mutant of tomato

Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms

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