MRC National Institute for Medical Research, London
Science for Health
Sly gene represses the sex chromosomes in the male mouse germline
17 November 2009
During spermatogenesis, germ cells progress through three phases to become functional sperm: proliferation, meiosis and spermiogenesis. In the latter phase, haploid germ cells (spermatids) undergo dramatic remodeling as they differentiate into spermatozoa. During meiosis the X and Y chromosomes are transcriptionally silenced and they retain a significant degree of repression after meiosis. This phenomenon is termed post-meiotic sex chromatin repression but is poorly characterized. Studies of mice with Y chromosome long arm deficiencies have suggested that the male-specific region of the Y chromosome (MSYq) encodes information required for sperm differentiation and post-meiotic sex chromatin repression. Several multicopy genes have been identified on MSYq, including one called Sly. Because these genes are present in more than 40 copies each, their functions cannot be investigated using traditional gene targeting.
Julie Cocquet, Shantha Mahadevaiah and Paul Burgoyne (pictured), in NIMR's Division of Stem Cell Biology & Developmental Genetics, have used an in vivo RNA interference approach to produce male mice with a dramatic reduction in Sly expression (shSLY mice). Microarray analyses have shown that these Sly-deficient males and also MSYq-deficient males exhibit a remarkable upregulation of sex chromosome genes in spermatids. The SLY protein co-localizes with the X and Y chromatin in the spermatids of normal males. Sly deficiency leads to defective repressive marks on the sex chromatin. SLY is consequently required for the recruitment and maintenance of the mediators of post-meiotic repression on sex chromatin. Sly-deficient mice, just like MSYq-deficient mice, have severe impairment of sperm differentiation and are near-sterile, probably as a consequence of the derepression of the sex chromatin. These results show that the key spermiogenic defects observed in MSYq- mice are also seen in shSLY mice, thus demonstrating that Sly deficiency is the underlying cause.
Gene amplification is a notable feature of the X and Y chromosomes, and it has been proposed that this serves to compensate for the post-meiotic repression. The data in this paper suggest that the repressive effect of Sly on post-meiotic X and Y genes drove their massive amplification in the mouse.
SLY protein is located in the spermatid nuclei in a stage-specific manner
Detection of SLY protein (green) by immunofluorescence in wild type testis sections. DAPI (white, or blue in the merged picture) was used to stain nuclei and lectin-PNA (red) was used to stain acrosomes in order to determine tubule stage. The inset on the right corner represents a 3.4x magnification.
SLY protein co-localizes with the X or the Y chromosome
In male post-meiotic germ cells (i.e. spermatids), SLY protein co-localizes with the X or the Y chromosome to repress transcription.
SLY has a predominant role in post-meiotic sex chromatin repression. Sly deficiency recapitulates almost all of the phenotypes observed in mice with MSYq deletions. Thus, Sly encodes the spermiogenesis factor identified 17 years ago on the Y long arm. Future studies of the many genes that we found differentially-expressed in shSLY mice will help in understanding the direct cause(s) of the multiple spermiogenesis defects observed in Sly- and MSYq-deficient mice. Here we have used transgenic delivery of siRNAs to disrupt the function of a multi-copy Y gene, and the same approach could be used for multi-copy genes on other chromosomes, for example Slx, a gene related to Sly.
Paul Burgoyne
Original article
The research findings are published in full in:
Julie Cocquet, Peter JI Ellis, Yasuhiro Yamauchi, Shantha K Mahadevaiah, Nabeel A Affara, Monika A Ward & Paul S Burgoyne (2009)
The multi-copy gene Sly represses the sex chromosomes in the male mouse germline after meiosis
PLoS Biology, 7(11): e1000244. Article full-text
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