Each time a cell divides, the small, stabilizing regions of DNA at the tips of our chromosomes—known as telomeres—get shorter; this phenomenon is linked to the fact that, eventually, most cells stop dividing and die. Past research led by David Keefe, chair of the Department of Obstetrics and Gynecology at the University of South Florida, in Tampa, Florida, suggests that telomere shortening may be a factor in the decline of women's fertility with age. Now, working with mice, Keefe's team has proven that the telomeres of egg cells (oocytes) do shorten with age—but they are also capable of lengthening, immediately after fertilization, by swapping around short pieces of DNA.1

In this study, published in a recent issue of Nature Cell Biology, Keefe wanted to understand how the shortening of telomeres in mature oocytes is overcome during development—a question that is relevant both to reproductive aging and to embryonic stem cell development. So his team first measured telomere length in individual mouse oocytes, zygotes and two-cell embryos using a technique called quantitative fluorescence in situ hybridization (Q-FISH). In addition to confirming that mature oocytes did have short telomeres, they discovered that telomeres lengthened significantly in one- and two-cell-stage embryos. They even observed this pattern in knockout mice that totally lack the enzyme telomerase, which is active later in embryonic development and appears to maintain telomere length.

Without telomerase, how were the telomeres getting longer? The researchers proposed that a well-known alternative lengthening mechanism, called telomere sister-chromatid exchange (T-SCE), was at work. T-SCE is a form of recombination and requires enzymes that can cut and paste DNA from one place to another. They tested for such enzymes using a different technique, chromosome orientation fluorescence in situ hybridization (CO-FISH), and discovered extensive T-SCE in early-cleavage-stage embryos. This proves that, at least in mice, newly fertilized eggs can make up for the short telomeres inherited from mature oocytes through a mechanism that is independent of the enzyme telomerase.

As well as adding to our fundamental understanding of early embryonic development, these findings have important implications for stem cell research. First, Keefe believes that the same biology that underlies the aging of egg cells will also prove to underlie aging in stem cells. Second, in order for differentiated adult cells to be reprogrammed as immortal pluripotent stem cells, their telomeres must elongate—otherwise the cells would be unable to divide and would die. But how does this happen? Keefe suggests that T-SCE is also responsible for telomere lengthening during reprogramming, just as it is in early embryonic development. Furthermore, he suspects that the inefficiency of the T-SCE mechanism may explain the inefficiencies in reprogramming somatic cells.