Spermatogenic failure in male mice with four sex chromosomes

There is accumulating evidence that meiosis, like mitosis, is monitored by a number of checkpoints. In mammals, the presence of asynapsed chromosomes at pachytene triggers a checkpoint (the pachytene or synapsis checkpoint) t hat removes cells via a p53-independent apoptotic pathway. In the special c ase of the sex bivalent in males, it is pseudoautosomal region (PAR) asynap sis that triggers the checkpoint. In male mice with three sex chromosomes ( XYY or XYY*(X)) some pachytene spermatocytes achieve full (trivalent) PAR s ynapsis, but in many cells one sex chromosome remains as a univalent, thus triggering the checkpoint. Sperm counts in these males have been shown to b e positively correlated with trivalent frequencies. In the present study sp erm production and levels of sex chromosome synapsis were studied in mice w ith four sex chromosomes (XYYY*(X) and XYY*Y-X*(X)). These mice proved to b e more severely affected than XYY or XYY*(X) mice. Nevertheless, pachytene synaptonemal complex analysis revealed that full PAR synapsis was achieved through the formation of radial quadrivalents or through the formation of t wo sex bivalents in 21%-49% of cells analysed. Given these levers of full P AR synapsis, the sperm counts were consistently lower than would have been predicted from the relationship between levels of PAR synapsis and sperm co unts in mice with three sex chromosomes. It has been suggested that the ina ctivation of the asynapsed non-PAR X and Y axes of the XY bivalent of norma l males (MSCI), which occurs during meiotic prophase, may be driven by Xist transcripts originating from the X. If this is the case, the non-PAR Y axe s of W and YY*(X) bivalents would fail to undergo MSCI. This could be cell lethal, either because of 'inappropriate' Y gene expression, or because the non-PAR Y axis may now trigger the synapsis checkpoint.