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Published online
doi:10.1083/jcb.200710195
The Journal of Cell Biology, Vol. 182, No. 2, 263-276
The Rockefeller University Press, 0021-9525 $30.00
© Mahadevaiah et al.
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Article

Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation



Shantha K. Mahadevaiah1, Déborah Bourc'his2, Dirk G. de Rooij3,4, Timothy H. Bestor5, James M.A. Turner1, and Paul S. Burgoyne1

1 Division of Stem Cell Biology and Developmental Genetics, Medical Research Council National Institute for Medical Research, London NW7 1AA, England, UK
2 Institut National de la Santé et de la Recherche Medicale U741, Institut Jacques Monod, 75251 Paris, Cedex 05, France
3 Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, Netherlands
4 Department of Endocrinology and Metabolism, Faculty of Science, Utrecht University, Utrecht 3584 CH, Netherlands
5 Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, NY 10032

Correspondence to Paul S. Burgoyne: pburgoy{at}nimr.mrc.ac.uk

Chromosome synapsis during zygotene is a prerequisite for the timely homologous recombinational repair of meiotic DNA double-strand breaks (DSBs). Unrepaired DSBs are thought to trigger apoptosis during midpachytene of male meiosis if synapsis fails. An early pachytene response to asynapsis is meiotic silencing of unsynapsed chromatin (MSUC), which, in normal males, silences the X and Y chromosomes (meiotic sex chromosome inactivation [MSCI]). In this study, we show that MSUC occurs in Spo11-null mouse spermatocytes with extensive asynapsis but lacking meiotic DSBs. In contrast, three mutants (Dnmt3l, Msh5, and Dmc1) with high levels of asynapsis and numerous persistent unrepaired DSBs have a severely impaired MSUC response. We suggest that MSUC-related proteins, including the MSUC initiator BRCA1, are sequestered at unrepaired DSBs. All four mutants fail to silence the X and Y chromosomes (MSCI failure), which is sufficient to explain the midpachytene apoptosis. Apoptosis does not occur in mice with a single additional asynapsed chromosome with unrepaired meiotic DSBs and no disturbance of MSCI.

Abbreviations used in this paper: ATR, ataxia telangiectasia and Rad3 related; BAC, bacterial artificial chromosome; DSB, double-strand break; MSCI, meiotic sex chromosome inactivation; MSUC, meiotic silencing of unsynapsed chromatin; SCD, SQ/TQ cluster domain.

© 2008 Mahadevaiah et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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