Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I

Infertility is a common feature of the human disorder ataxia-telangiectasia and Aml-deficient mice are completely infertile, To gain further insight i nto the role of ATM in meiosis, we examined meiotic cells in Atm-deficient mice during development. Spermatocyte degeneration begins between postnatal days 8 and 16.5, soon after entry into prophase I of meiosis, while oocyte s degenerate late in embryogenesis prior to dictyate arrest. Using electron microscopy and immunolocalization of meiotic proteins in mutant adult sper matocytes, we found that male and female gametogenesis is severely disrupte d in Atm-deficient mice as early as leptonema of prophase I, resulting in a poptotic degeneration, A small number of mutant cells progress into later s tages of meiosis, but no cells proceed beyond prophase I. ATR, a protein re lated to ATM, DMC1, a RAD51 family member, and RAD51 are mislocalized to ch romatin and have reduced localization to developing synaptonemal complexes in spermatocytes from At,ll-deficient mice, suggesting dysregulation of the orderly progression of meiotic events. ATM protein is normally present at high levels primarily in ova cytoplasm of developing ovarian follicles, and in the nucleus of spermatogonia and to a lesser extent in spermatoctyes, b ut without localization to the synaptonemal complex. We propose a model in which ATM acts to monitor meiosis by participation in the regulation or sur veillance of meiotic progression, similar to its role as a monitor of mitot ic cell cycle progression.