Clumsy Chromosomes: Matchmaking protein might reveal causes of age-related infertility (Birth defects; Reproduction)
Authors: Leslie Mitch 
Published: August 2003

Just as a baseball team needs nine players, a human embryo needs 46 chromosomes, because extra or missing ones can derail development. Researchers have now identified a protein that helps guarantee the right number of chromosomes in an egg. The results might lead to the first animal model for studying an abnormality that hits women as they age and that underlies many cases of infertility, miscarriages, and birth defects.

A nonstandard number of chromosomes is known as aneuploidy, and the risk for eggs soars with maternal age. About half of the eggs from a woman in her 40s are affected, says Terry Hassold, a chromosome biologist at Case Western Reserve University in Cleveland, Ohio. Aneuploidy results from the failure of chromosomes to disengage during meiosis, the process that produces sperm and eggs. Early in meiosis, chromosomes line up side by side like dance partners. Pairing not only allows the strands to intertwine and swap segments, it ensures that the chromosomes have gone their separate ways by the time meiosis concludes. A multipart protein machine helps chaperone the chromosomes into position, and a protein--SCP3--helps construct that molecular usher. Three years ago, Christer Höög, a cell biologist at the Karolinska Institute in Stockholm, Sweden, and colleagues showed that male mice lacking SCP3 were sterile because their sperm perish, but the protein's effects on eggs were unknown.

Yuan and colleagues now report how SCP3 influences female fertility. They allowed normal female mice and those that lack the
SCP3
gene to mate with healthy males. Compared with the control group, the knockout females carried many more defunct embryos and produced nearly one-third fewer offspring. Observations of maturing eggs from knockout females indicated that the chromosomes didn't line up correctly. For example, early in meiosis half of these eggs contained solitary chromosomes. And the paired chromosomes did not join as tightly as in normal eggs, which could explain how SCP3 deficiency leads to aneuploidy. The experiments are the first to generate aneuploidy in mice, and the SCP3-deficient rodents might model the link between aging and aneuploidy in humans, says Höög, senior author of the paper. The chance that a mouse embryo will die rises with the mother's age. By analogy with humans, he says, this result suggests that reduced survival rates might stem from a surge in aneuploidy. In addition, the findings raise the possibility that defects in SCP3 cause some cases of aneuploidy in women, he adds.

Hassold pronounces the results promising. But before putting these mice to work, he says, scientists need to undertake painstaking studies to demonstrate that aneuploidy does lower embryo survival in the knockout animals, something that the authors only infer. The need for an animal model of aneuploidy grows as more women postpone childbirth until their late 30s or 40s, says human geneticist Wendy Robinson of the University of British Columbia in Vancouver, Canada. The mice might also allow scientists to test whether suspected egg-damaging compounds such as caffeine and folic acid trigger aneuploidy, she says. Mice lacking SCP3 might not bat 1.000 as human substitutes, but perhaps they'll make good pinch hitters.

--Mitch Leslie

L. Yuan, J.-G. Liu, M.-R. Hoja, J. Wilbertz, K. Nordqvist, C. Höög, Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3.
Science
296
, 1115-1118 (2002).
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