Researchers have a new understanding of the process cells use to ensure that sperm and eggs begin life with exactly one copy of each chromosome - a process that must be exquisitely regulated to prevent problems such as miscarriages and mental retardation.
The new work reveals how gluelike protein complexes release pairs of chromosomes at precisely the moment of meiosis - the specialized cell division process that produces sperm and eggs - enabling them to separate properly.
The researchers, led by Howard Hughes Medical Institute investigator Angelika Amon, published their findings online May 3, 2006, in the journal Nature. Amon and her colleagues are at the Massachusetts Institute of Technology.
Most cells in the human body - all those other than sperm and eggs - contain 23 pairs of chromosomes. These cells divide through mitosis, a process that creates daughter cells with the same complement of chromosome pairs as the parent. Sperm and egg cells, on the other hand, must contain only half the chromosomes of their parent cells, so that the normal chromosome number will be restored when the sperm and egg unite during fertilization. To achieve this, they are produced through meiosis.
Gluelike protein complexes called cohesins, which hold the members of a chromosome pair together until just the right moment during cell division, are central to both processes. Bound together by cohesins, chromosome pairs must organize themselves in preparation for cell division before they can be released.
According to Amon, a deeper basic knowledge of the mechanism of cohesin loss during meiosis could ultimately improve understanding of the origins of miscarriages and mental retardation due to mis-segregation of chromosomes.
"We first need to understand the key regulatory players and the molecular mechanisms that cause chromosomes to segregate in this very unusual way during meiosis," she said. "Once we have a good enough understanding, then we can ask, for example, what exactly happens to cohesins in older women that make them more likely to give birth to children with an abnormal chromosome number."
According to Amon, knowledge about the mechanism of cohesin function has remained sketchy, even though it plays a central role in meiosis. Researchers knew that an enzyme called separase snips apart cohesins, targeting a specific subunit of the cohesin complex called Rec8. Also, she said, researchers had found that Rec8 cleavage was promoted by phosphorylation -- the addition of chemical phosphate groups -- of Rec8.
Researchers also knew that cohesins release chromosome pairs from one another's embrace quite differently during meiosis and mitosis. In mitosis, cohesins release chromosomes along their entire length simultaneously. However, in the initial stage of meiosis, cohesins first release only the "arms" of chromosomes, still holding the chromosomes together at their central connection point, the centromere. Only in a second stage of meiosis that gives rise to haploid sperm or egg cells do centromeric cohesins become cleaved. This precisely controlled centromeric "stickiness" is essential for the accurate segregation of sister chromatids into separate cells.
"The key question we wanted to explore was how this step-wise loss of cohesins in meiosis was regulated," said Amon. "It could be that the enzyme separase was the key regulatory player, or it could be that it was the phosphorylation of cohesins that was central."