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

Abstract

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.

Meiotic spindle assembly checkpoint and aneuploidy in males versus females

“…Interestingly, genes whose heterozygosity produced aneuploid splenocytes ( Bub3 , Rae1 , Bub3 / Rae1 double heterozygotes and Rae1 / Nup98 double heterozygotes) did not show such effect in spermatocytes [52]. Thus far, the only mouse models where reduced SAC protein levels have been shown to result in lower SAC fidelity in male meiosis are BubR1 hypomorphs [53] and Mad2 heterozygotes [54] (Table 1).…”