Sex chromosome recombination failure, apoptosis, and fertility in male mice

Faisal, Imrul; Kauppi, Liisa

doi:10.1007/s00412-015-0542-9

Cited by 22 publications

(31 citation statements)

References 26 publications

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“…To examine whether disruption of one Mad2 allele affects sex chromosome pairing in Spo11β-only mb mice, we scored X-Y pairing frequency in pachytene spermatocytes of Mad2 +/− Spo11β-only mb mice. As previously seen in Spo11β-only mb spermatocytes (Faisal and Kauppi, 2016), we found two distinct classes of pachytene stage nuclei: those with X and Y chromosomes paired (Fig. 3Bi); and those with X and Y chromosomes separated (Fig.…”

Section: Prophase I Progressionsupporting

confidence: 85%

“…X and Y chromosomes were paired in 52% of Mad2 +/− Spo11β-only mb pachytene nuclei ( Fig. 3C), which was indistinguishable from Spo11β-only mb mice (Faisal and Kauppi, 2016). This is in contrast to control mice, where X and Y PARs were paired in 97% of pachytene nuclei.…”

Section: Prophase I Progressionmentioning

confidence: 84%

“…Of its two main isoforms, SPO11α and SPO11β (Keeney et al, 1997(Keeney et al, , 1999Romanienko and Camerini-Otero, 1999;Bellani et al, 2010), the former is dispensable for autosomal double-strand break formation and recombination but is required for efficient X-Y recombination (Kauppi et al, 2011(Kauppi et al, , 2012. Depending on the genetic background, between 30 and 50% of spermatocytes of mice lacking SPO11α (Spo11β-only mice) accomplish PAR pairing and recombination (Kauppi et al, 2011;Faisal and Kauppi, 2016). We have shown previously that Spo11β-only males on a mixed genetic background (Spo11β-only mb ), despite having 50% of pachytene spermatocytes with X-Y pairing failure, are able to maintain sperm production and fertility (Faisal and Kauppi, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Depending on the genetic background, between 30 and 50% of spermatocytes of mice lacking SPO11α (Spo11β-only mice) accomplish PAR pairing and recombination (Kauppi et al, 2011;Faisal and Kauppi, 2016). We have shown previously that Spo11β-only males on a mixed genetic background (Spo11β-only mb ), despite having 50% of pachytene spermatocytes with X-Y pairing failure, are able to maintain sperm production and fertility (Faisal and Kauppi, 2016). Nevertheless, we also observed many apoptotic metaphase I cells in Spo11β-only mb testes, suggesting that spermatocytes with non-exchange X-Y chromosomes trigger a SAC response and, consequently, are eliminated (Faisal and Kauppi, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…We have shown previously that Spo11β-only males on a mixed genetic background (Spo11β-only mb ), despite having 50% of pachytene spermatocytes with X-Y pairing failure, are able to maintain sperm production and fertility (Faisal and Kauppi, 2016). Nevertheless, we also observed many apoptotic metaphase I cells in Spo11β-only mb testes, suggesting that spermatocytes with non-exchange X-Y chromosomes trigger a SAC response and, consequently, are eliminated (Faisal and Kauppi, 2016). Thus, this presumably SAC-mediated quality control helps to eliminate spermatocytes with achiasmate (non-exchange) chromosomes at metaphase I, similar to observations made by Eaker and colleagues in a mouse model with heterozygous Robertsonian translocations (Eaker et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Reduced MAD2 levels dampen the apoptotic response to non-exchange sex chromosomes and lead to sperm aneuploidy

Faisal¹,

Kauppi²

2017

Journal of Cell Science

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In meiosis, non-exchange homologous chromosomes are at risk for mis-segregation and should be monitored by the spindle assembly checkpoint (SAC) to avoid formation of aneuploid gametes. Sex chromosome mis-segregation is particularly common and can lead to sterility or to aneuploid offspring (e.g. individuals with Turner or Klinefelter syndrome). Despite major implications for health and reproduction, modifiers of meiotic SAC robustness and the subsequent apoptotic response in male mammals remain obscure. Levels of SAC proteins, e.g. MAD2, are crucial for normal checkpoint function in many experimental systems, but surprisingly, apparently not in male meiosis, as indicated by the lack of chromosome segregation defects reported earlier in Mad2 +/− spermatocytes. To directly test whether MAD2 levels impact the meiotic response to missegregating chromosomes, we used Spo11β-only mb mice that are prone to non-exchange X-Y chromosomes. We show that reduced MAD2 levels attenuate the apoptotic response to mis-segregating sex chromosomes and allow the formation of aneuploid sperm. These findings demonstrate that SAC protein levels are crucial for the efficient elimination of aberrant spermatocytes.

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Section: Prophase I Progressionsupporting

confidence: 85%

Section: Prophase I Progressionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Reduced MAD2 levels dampen the apoptotic response to non-exchange sex chromosomes and lead to sperm aneuploidy

Faisal¹,

Kauppi²

2017

Journal of Cell Science

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The proper interplay between the expression of Spo11 splice isoforms and the structure of the pseudoautosomal region promotes XY chromosomes recombination

Giannattasio,

Testa,

Faieta

et al. 2023

Cell. Mol. Life Sci.

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XY chromosome missegregation is relatively common in humans and can lead to sterility or the generation of aneuploid spermatozoa. A leading cause of XY missegregation in mammals is the lack of formation of double-strand breaks (DSBs) in the pseudoautosomal region (PAR), a defect that may occur in mice due to faulty expression of Spo11 splice isoforms. Using a knock-in (ki) mouse that expresses only the single Spo11β splice isoform, here we demonstrate that by varying the genetic background of mice, the length of chromatin loops extending from the PAR axis and the XY recombination proficiency varies. In spermatocytes of C57Spo11βki/− mice, in which loops are relatively short, recombination/synapsis between XY is fairly normal. In contrast, in cells of C57/129Spo11βki/− males where PAR loops are relatively long, formation of DSBs in the PAR (more frequently the Y-PAR) and XY synapsis fails at a high rate, and mice produce sperm with sex-chromosomal aneuploidy. However, if the entire set of Spo11 splicing isoforms is expressed by a wild type allele in the C57/129 background, XY recombination and synapsis is recovered. By generating a Spo11αki mouse model, we prove that concomitant expression of SPO11β and SPO11α isoforms, boosts DSB formation in the PAR. Based on these findings, we propose that SPO11 splice isoforms cooperate functionally in promoting recombination in the PAR, constraining XY asynapsis defects that may arise due to differences in the conformation of the PAR between mouse strains.

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Recent advances in mechanisms ensuring the pairing, synapsis and segregation of XY chromosomes in mice and humans

Lampitto,

Barchi

2024

Cell. Mol. Life Sci.

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Sex chromosome aneuploidies are among the most common variations in human whole chromosome copy numbers, with an estimated prevalence in the general population of 1:400 to 1:1400 live births. Unlike whole-chromosome aneuploidies of autosomes, those of sex chromosomes, such as the 47, XXY aneuploidy that causes Klinefelter Syndrome (KS), often originate from the paternal side, caused by a lack of crossover (CO) formation between the X and Y chromosomes. COs must form between all chromosome pairs to pass meiotic checkpoints and are the product of meiotic recombination that occurs between homologous sequences of parental chromosomes. Recombination between male sex chromosomes is more challenging compared to both autosomes and sex chromosomes in females, as it is restricted within a short region of homology between X and Y, called the pseudo-autosomal region (PAR). However, in normal individuals, CO formation occurs in PAR with a higher frequency than in any other region, indicating the presence of mechanisms that promote the initiation and processing of recombination in each meiotic division. In recent years, research has made great strides in identifying genes and mechanisms that facilitate CO formation in the PAR. Here, we outline the most recent and relevant findings in this field. XY chromosome aneuploidy in humans has broad-reaching effects, contributing significantly also to Turner syndrome, spontaneous abortions, oligospermia, and even infertility. Thus, in the years to come, the identification of genes and mechanisms beyond XY aneuploidy is expected to have an impact on the genetic counseling of a wide number of families and adults affected by these disorders.

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Sex chromosome recombination failure, apoptosis, and fertility in male mice

Cited by 22 publications

References 26 publications

Reduced MAD2 levels dampen the apoptotic response to non-exchange sex chromosomes and lead to sperm aneuploidy

Reduced MAD2 levels dampen the apoptotic response to non-exchange sex chromosomes and lead to sperm aneuploidy

The proper interplay between the expression of Spo11 splice isoforms and the structure of the pseudoautosomal region promotes XY chromosomes recombination

Recent advances in mechanisms ensuring the pairing, synapsis and segregation of XY chromosomes in mice and humans

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