Atm Inactivation Results in Aberrant Telomere Clustering during Meiotic Prophase

Abstract

A-T (ataxia telangiectasia) individuals frequently display gonadal atrophy, and Atm^−/− mice show spermatogenic failure due to arrest at prophase of meiosis I. Chromosomal movements take place during meiotic prophase, with telomeres congregating on the nuclear envelope to transiently form a cluster during the leptotene/zygotene transition (bouquet arrangement). Since the ATM protein has been implicated in telomere metabolism of somatic cells, we have set out to investigate the effects of Atm inactivation on meiotic telomere behavior. Fluorescent in situ hybridization and synaptonemal complex (SC) immunostaining of structurally preserved spermatocytes I revealed that telomere clustering occurs aberrantly in Atm^−/− mice. Numerous spermatocytes of Atm^−/− mice displayed locally accumulated telomeres with stretches of SC near the clustered chromosome ends. This contrasted with spermatogenesis of normal mice, where only a few leptotene/zygotene spermatocytes I with clustered telomeres were detected. Pachytene nuclei, which were much more abundant in normal mice, displayed telomeres scattered over the nuclear periphery. It appears that the timing and occurrence of chromosome polarization is altered in Atm^−/− mice. When we examined telomere-nuclear matrix interactions in spermatocytes I, a significant difference was observed in the ratio of soluble versus matrix-associated telomeric DNA sequences between meiocytes of Atm^−/− and control mice. We propose that the severe disruption of spermatogenesis during early prophase I in the absence of functional Atm may be partly due to altered interactions of telomeres with the nuclear matrix and distorted meiotic telomere clustering.

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Atm Inactivation Results in Aberrant Telomere Clustering during Meiotic Prophase

ACKNOWLEDGMENTS

This study was supported by NIH grant NS34746 and by Deutsche Forschungsgemeinschaft grant Sche 350/8-2.

Thanks are due to P. Leder, Harvard Medical School, Boston, Mass., for providing mating pairs of Atm heterozygote mice; to Lubomir Smilenov for technical help; and to C. Heyting, Wageningen, The Netherlands, for providing SCP3 antiserum. Thanks are also due to A. Wynshaw-Boris and T. Ashley for their comments.