MRC National Institute for Medical Research, London
Science for Health
Sex chromosome silencing and infertility
03 December 2010
Spermatogenesis is the process in which stem cells differentiate to form mature sperm. Midway through spermatogenesis, germ cells undergo a specialized cell division called meiosis, during which chromosomes pair and exchange genetic information. The sex chromosomes, called the X and Y chromosomes, are unusual in that they remain unpaired during normal meiosis. This lack of pairing leads to inactivation of X- and Y-genes, a process called Meiotic Sex Chromosome Inactivation (MSCI). MSCI is highly conserved in the animal kingdom, being observed in a broad array of organisms ranging from flies to worms to mammals, but whether it is required for spermatogenesis is unclear.
In a new study, James Turner (pictured) and his lab, in collaboration with Paul Burgoyne, both in NIMR’s Division of Stem Cell Biology and Developmental Genetics, has provided experimental evidence revealing that MSCI is indeed essential for germ cells to complete spermatogenesis. To show this, they have used the XYY mouse, which has two copies rather than one copy of the Y chromosome. They found that the presence of the second Y allowed the two Y chromosomes to pair during meiosis. This pairing prevented the Y chromosomes from undergoing MSCI. Interestingly, the resulting continual expression of Y chromosomal genes triggered a complete arrest in spermatogenesis, specifically during meiosis. The group went on to demonstrate that the cause of this germ cell arrest could be narrowed down to the expression of a specific gene on the Y chromosome called Zfy1/2.
As well as showing that silencing of sex chromosome genes is important for spermatogenesis, the findings are highly relevant to our understanding of infertility in patients with sex chromosome disorders. A number of XYY men are infertile, and ZFY is also found on the human Y chromosome. We would predict that a major factor contributing to infertility in these men is Y-Y pairing during meiosis, with the resulting persistent expression of Y-chromosomal genes, including ZFY, being toxic to meiotic cells.
James Turner
Original article
Hélène Royo, Grzegorz Polikiewicz, Shantha K. Mahadevaiah, Haydn Prosser, Mike Mitchell, Allan Bradley, Dirk G. de Rooij, Paul S. Burgoyne, and James M.A. Turner (2010)
Evidence that Meiotic Sex Chromosome Inactivation is Essential for Male Fertility
Current Biology, Epub ahead of print. PubMed abstract.
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