Sacrificing immature eggs for the greater good
A woman's supply of eggs is a precious commodity because only a few hundred will be produced throughout her lifetime and hopefully as free as possible from genetic damage.
Part of egg production involves winnowing the woman's supply during her own fetal development. New research by Alex Bortvin and postdoctoral fellow Safia Malki of the Carnegie Institution for Science, has provided new insight into the fetal stage of egg selection.
Their work appears in the early on-line edition of Developmental Cell.
Before a baby girl is born she has lost 80 percent of her initial pool of immature eggs. This phenomenon has been observed in primates and rodents, as well as some invertebrates, indicating a long evolutionarily past. But despite its ancient origins, little is understood about how the selection process is made.
Bortvin's team discovered that fetal egg die-off is connected to "jumping genes" or the transposable elements found in an egg's DNA.
As developing eggs mature, transposons start to move. These ancient virus-like genes begin to leapfrog around the DNA of an egg — producing mutations. Transposon elements (TE) are a DNA sequence that can change position within the genome, sometimes creating or reversing mutations and altering a cell's genome size. Transposition often results in duplication of the TE. Barbara McClintock, PhD, discovered these jumping genes in 1983 earning her a Nobel prize.
Jumping genes can be particularly destructive in sperm and eggs.
Prior studies have shown that male germ cells quash the movement of transposons, minimizing sperm mutations and ensuring high levels of sperm production.
In contrast, mouse eggs accommodate to transposon movement by eliminating immature eggs (which harbor the highest number of mutations) before the female mouse is born. Bortvin's team proposes this purge of immature eggs allows for survival of eggs whose genetic material has relatively few mutations.
But Bortvin's group also found that purging immature eggs must be finely balanced. Overly stringent purging could result in too few surviving eggs, or premature loss of fertility. Purging that is not stringent enough could allow eggs with a lot of jumping gene-related errors to survive, leading to high levels of birth defects.
Bortvin: "Our findings suggest that the ovary of a newborn girl already contains both 'good' eggs and those which will miscarry. Further study may show that these 'good' cells are ovulated first and abnormal ones later."
Bortvin and Malki discovered that the drug AZT, which inhibits multiplication of AIDS-causing HIV virus in humans, also can alter jumping gene activity in immature eggs.
Ii is particularly effective against LINE1 (L1) transposons found in mammals.
This raises the possibility that the number and quality of immature eggs might be enhanced by drug treatment aimed at L1 transposons.
Despite the destructive power of jumping genes, they might also provide genetic flexibility in a species needing to adapt quickly to survive a new environment. By allowing just the right amount of beneficial transposon-generated genetic variation, female mammals may be giving their own offspring and their entire species the best chance of thriving in a dangerous world.
•Differential nuclear retrotransposon L1 levels in meiotic prophase I fetal oocytes
•Increased L1 expression precipitates oocyte genome damage and meiotic defects
•AZT implicates RNA/DNA hybrids in triggering oocyte death and chiasma failure
•L1 activity underlies fetal oocyte attrition, reduced ovarian reserves, and aneuploidy
Fetal oocyte attrition (FOA) is a conserved but poorly understood process of elimination of more than two-thirds of meiotic prophase I (MPI) oocytes before birth. We now implicate retrotransposons LINE-1 (L1), activated during epigenetic reprogramming of the embryonic germline, in FOA in mice. We show that wild-type fetal oocytes possess differential nuclear levels of L1ORF1p, an L1-encoded protein essential for L1 ribonucleoprotein particle (L1RNP) formation and L1 retrotransposition. We demonstrate that experimental elevation of L1 expression correlates with increased MPI defects, FOA, oocyte aneuploidy, and embryonic lethality. Conversely, reverse transcriptase (RT) inhibitor AZT has a profound effect on the FOA dynamics and meiotic recombination, and it implicates an RT-dependent trigger in oocyte elimination in early MPI. We propose that FOA serves to select oocytes with limited L1 activity that are therefore best suited for the next generation.
This work was supported by the endowment of Carnegie Institution for Science, by a CPRIT R1101 award, and by NIH grant GM40367. Researchers were supported by an EMBO long-term fellowship and a McClintock fellowship as well as a Hollaender fellowship.
The Carnegie Institution for Science is a private, nonprofit organization headquartered in Washington, D.C., with six research departments throughout the U.S. Since its founding in 1902, the Carnegie Institution has been a pioneering force in basic scientific research. Carnegie scientists are leaders in plant biology, developmental biology, astronomy, materials science, global ecology, and Earth and planetary science.
Return to top of page