Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2

The initiation of chromosome segregation at anaphase is linked by the spind le assembly checkpoint to the completion of chromosome-microtubule attachme nt during metaphase. To determine the function of the mitotic checkpoint pr otein Mad2 during normal cell division and when mitosis goes awry, we have knocked out Mad2 in mice. We find that E5.5 embryonic cells lacking Mad2, l ike mad2 yeast, grow normally but are unable to arrest in response to spind le disruption. At E6.5, the cells of the epiblast begin rapid cell division and the absence of a checkpoint results in widespread chromosome missegreg ation and apoptosis. In contrast, the postmitotic trophoblast giant cells s urvive without Mad2. Thus, the spindle assembly checkpoint is required for accurate chromosome segregation in mitotic mouse cells, and for embryonic v iability, even in the absence of spindle damage.