Sci. Aging Knowl. Environ., 21 April 2004
Vol. 2004, Issue 16, p. nf42
[DOI: 10.1126/sageke.2004.16.nf42]


Illegal Formation

Stubby telomeres upset chromosome pairing in sperm and eggs

Mitch Leslie

The biological clock that counts down a woman's childbearing years might be sitting on the ends of her chromosomes. A new study suggests that dwindling telomeres disrupt chromosomal liaisons necessary for making sperm and eggs. The results could help explain why infertility rates rise as women grow older.

Telomeres, the protective caps at the ends of chromosomes, shrink with each cell division. Puny telomeres allow chromosomes to fuse and provoke other problems (see "More Than a Sum of Our Cells"), and many researchers suspect that they also curtail reproduction. For example, the shorter the telomeres in a woman's eggs, the less likely she'll get pregnant through in vitro fertilization, says David Keefe, a reproductive medicine physician at Brown Medical School in Providence, Rhode Island. The problem might arise during meiosis, the series of cell divisions that make eggs and sperm. Early in meiosis, matching chromosomes line up. Unless this pairing occurs correctly, a sperm or egg can receive the wrong number of chromosomes, which can kill the cell or lead to offspring with abnormalities such as Down syndrome. Telomeres help chromosomes find their partners in the tangle of DNA by anchoring the strands to the nuclear membrane.

To determine whether truncated telomeres bollix chromosome pairing, Keefe and colleagues studied genetically altered mice that lacked the telomere-replenishing enzyme telomerase and sported chromosome caps that were about half the normal length. The researchers removed developing sperm and incipient eggs from the mice and tested for the presence of a protein called SCP3, which helps form a molecular zipper between aligned chromosomes. They found fewer sperm and eggs with SCP3 in engineered rodents than in control mice. Moreover, five times as many protosperm had killed themselves in the altered group, a sign that the cells carried chromosome defects. Eggs rarely showed molecular traces of suicide, the team found. However, the altered animals had fewer eggs, suggesting that the cells had seized up during division, another indicator of raddled DNA. Eggs and sperm in the engineered rodents contained fewer sites where adjacent chromosomes had intertwined, indicating that the strands had not lined up properly. Together, the results suggest that telomere shrinkage hampers the chromosome coupling necessary for normal sperm and egg development.

The finding might explain declining fertility rates in older women, says Keefe. Old eggs might lose telomeres from decades of exposure to oxidants or because the "production line" for making eggs in the embryo ensures that eggs that mature late in life have undergone more divisions than those released earlier have. Men are insulated from the problem because, unlike developing eggs, developing sperm make telomerase.

"It's a very stimulating paper," says cytologist Harry Scherthan of the Max Planck Institute for Molecular Genetics in Berlin, Germany. However, he says that the work doesn't pin the blame for faulty chromosome pairing on truncated telomeres. Although the mice's telomeres are short, they are longer than normal human telomeres--and big enough to do their job, he argues. Keefe responds that telomeres might malfunction at different lengths in the two species. Further research will help determine whether telomeres make the biological clock tick.

April 21, 2004

Suggested by Patrick Kaminker.

  1. L. Liu et al., Irregular telomeres impair meiotic synapsis and recombination in mice. Proc. Natl. Acad. Sci. U.S.A., 14 April 2004 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: M. Leslie, Illegal Formation. Sci. Aging Knowl. Environ. 2004 (16), nf42 (2004).

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