Meiotic Chromosome Behavior in a Human Male t(8;15) Carrier
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Synapsis
Synaptonemal complex
Chromosomal rearrangement
Spermatocyte
Spermatogenic cells synthesize a unique 70-kDa heat shock protein (HSP70-2) during prophase of meiosis I, and targeted disruption of the Hsp70-2 gene has shown that this protein is required for spermatogenic cell differentiation in adult mice. HSP70-2 is associated with synaptonemal complexes formed between paired homologous chromosomes during meiotic prophase. The present study focuses on the nearly synchronous first wave of spermatogenesis in 12- to 28-day old juvenile mice to determine more precisely when HSP70-2 is required and what meiotic processes are affected by its absence. Spermatogenesis in homozygous mutant mice (Hsp70-2[-/-]) proceeded normally until day 15 when increasing numbers of pachytene spermatocytes became apoptotic and differentiation of cells beyond the pachytene stage began to falter. Synaptonemal complexes assembled in Hsp70-2(-/-) mice and spermatocytes developed through the final pachytene substage. However, synaptonemal complexes failed to desynapse and normal diplotene spermatocytes were not observed. Metaphase spermatocytes were not seen in tissue sections from testes of Hsp70-2(-/-) mice, and expression of mRNAs and antigens characteristic of late pachytene spermatocytes (e.g., cyclin A1) and development of spermatids did not occur. Thus, HSP70-2 is required for synaptonemal complex desynapsis, and its absence severely impairs the transition of spermatogenic cells through the late meiotic stages and results in apoptosis beginning with the first wave of germ cell development in juvenile mice.
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During the first meiotic prophase, the cohesin complex is localized to the chromosome axis and contributes to chromosome organization, pairing, synapsis, and recombination. The PDS5 protein, an accessory factor of the cohesin complex, is known to be a component of meiotic chromosome cores in fungi and to be implicated in meiotic chromosome structure and function. We found by immunoblotting experiments that a mammalian PDS5 protein, PDS5B, is abundantly expressed in mouse testis compared to other tissues. Immunofluorescence labeling experiments revealed that PDS5B is highly expressed in spermatogonia and that most PDS5B is depleted from chromatin as cells enter meiosis. During the first meiotic prophase, PDS5B associates with the axial cores of chromosomes. The axial association of PDS5B was observed also in the absence of synaptonemal complex proteins, such as SYCP1 and SYCP3, suggesting that PDS5B is an integral part of the chromosome axis as defined by the cohesin complex. These results suggest that PDS5B modulates cohesin functions in spermatocytes as well as in spermatogonia, contributing to meiotic chromosome structure and function.
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Meiotic prophase I is a prolonged G2 phase that ensures the completion of numerous meiosis-specific chromosome events. During meiotic prophase I, homologous chromosomes undergo synapsis to facilitate meiotic recombination yielding crossovers. It remains largely elusive how homolog synapsis is temporally maintained and destabilized during meiotic prophase I. Here we show that FBXO47 is the stabilizer of the synaptonemal complex during male meiotic prophase I. Disruption of FBXO47 shows severe impact on homologous chromosome synapsis, meiotic recombination, and XY body formation, leading to male infertility. Notably, in the absence of FBXO47, although once homologous chromosomes are synapsed, the synaptonemal complex is precociously disassembled before progressing beyond pachytene. Remarkably, Fbxo47 KO spermatocytes remain in an earlier stage of meiotic prophase I and lack crossovers, despite apparently exhibiting diplotene-like chromosome morphology. We propose that FBXO47 plays a crucial role in preventing the synaptonemal complex from premature disassembly during cell cycle progression of meiotic prophase I.
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Summary Analysis of the N ‐ethyl‐ N ‐nitrosourea ( ENU )‐induced repro42 mutation previously identified spermatogenesis associated 22 ( Spata22 ) as a gene required for meiotic progression and fertility in both male and female mice, but its specific contribution to the process was unclear. Here, we report on a novel, null allele of Spata22 ( Spata22 Gt ) and confirm its requirement for germ cell development. Similar to repro42 mutant mice, histological and mating analyses indicate that gametogenesis is profoundly affected in Spata22 Gt/Gt males and females, resulting in infertility. Cytological examination confirms that germ cells do not progress beyond zygonema and meiotic arrest is linked to impairment of both synapsis and DNA repair. Analysis of SPATA 22 distribution reveals that it localizes to foci associated with meiotic chromosomes during prophase I and that the number of foci peaks at zygonema; there are also more SPATA 22 foci in oocytes than in spermatocytes. Furthermore, SPATA 22 co‐localizes with a number of proteins involved in meiotic recombination, including RAD 51, DMC 1, and MLH 1, and is present until mid‐pachynema, suggesting a role in resolution of recombination intermediates. In fact, SPATA 22 co‐localizes with MLH 1 in more than 20% of foci at pachynema. Analysis of Spata22 Gt/Gt meiocytes confirms that SPATA 22 is required for localization of MEIOB but not RPA (two proteins known to interact with SPATA 22), and immunoblotting corroborates that production of MEIOB is indeed decreased in the absence of SPATA 22. Together, these data suggest that SPATA 22 is required for both meiotic recombination and synapsis during meiosis in mice.
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Synapsis
Synaptonemal complex
Spermatocyte
Chromosome pairing
Bivalent (engine)
Human genetics
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Synapsis
Spermatocyte
Synaptonemal complex
Bivalent (engine)
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Synapsis
Synaptonemal complex
Chromosomal rearrangement
Spermatocyte
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To prevent chromosomal aberrations to be transmitted to the offspring, strict meiotic checkpoints are in place to remove aberrant spermatocytes. However, in about 1% of all males these checkpoints cause complete meiotic arrest leading to azoospermia and subsequent infertility. We here unravel two clearly distinct meiotic arrest mechanisms that act during the prophase of human male meiosis. Type I arrested spermatocytes display severe asynapsis of the homologous chromosomes, disturbed XY-body formation and increased expression of the Y-chromosome encoded gene ZFY and seem to activate a DNA damage pathway leading to induction of p63, possibly causing spermatocyte apoptosis. Type II arrested spermatocytes display normal chromosome synapsis, normal XY-body morphology and meiotic crossover formation but have a lowered expression of several cell cycle regulating genes and fail to properly silence the X-chromosome encoded gene ZFX. Discovery and understanding of these meiotic arrest mechanisms increases our knowledge on how genomic stability is guarded during human germ cell development.
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Synaptonemal complex
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Synapsis
Synaptonemal complex
Spermatocyte
Bivalent (engine)
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