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GENETICS Formin Gene May Explain a Common Cause of Female Infertility Ubiquitous proteins of the cell skeleton, such as actin and tubulin, mediate a wide range of cellular activities, including the positioning of the metaphase DNA-spindle, a key step in egg cell development. But what happens when the cytoskeleton fails to regulate spindle movement? One result is the production of egg cells with an abnormal number of chromosomes, the leading cause of pregnancy loss and a major contributor to birth defects and female infertility. A recent discovery, the function of a previously identified formin gene, Fmn2, may help explain recurrent pregnancy loss, a condition that affects millions of women throughout the world. Philip Leder and Benjamin Leader (l to r) have discovered that oocytes from female mice without the formin gene Fmn2 cannot correctly position the metaphase I DNA-spindle. This produces daughter cells with an abnormal number of chromosomes, the leading cause of female infertility, birth defects, and embryo loss. (Photo by Steve Gilbert) HMS researchers have found that oocytes of female mice without Fmn2, which produces the protein formin-2, were unable to correctly position the DNA-spindle during meiosis I, a handicap that led to severe pregnancy complications. The work was performed in the laboratory of Philip Leder, the John Emory Andrus professor of genetics and chair of the Department of Genetics, who discovered formins in 1990. Genes of the formin family, including Fmn2, are expressed in almost all organisms and have been implicated in cell polarity and cytoskeletal organization. A recent discovery, the function of a previously identified formin gene, Fmn2, may help explain recurrent pregnancy loss, a condition that affects millions of women throughout the world. For decades, scientists have observed that in a normal cell undergoing meiosis, disruption of the microtubule-based spindle causes chromosomes to migrate to the cortex. Yet the underlying mechanism has remained elusive. "Here was a previously described phenomenon that had no known genetic basis, and we found that Fmn2 was involved in it," explained Benjamin Leader, an HMS MD-PhD student and first author of the paper, which appears in the December Nature Cell Biology. When he and colleagues deliberately disrupted the spindle in Fmn2-deficient eggs, they found the chromosomes remained stuck in the middle, suggesting that without the gene, the eggs lost their ability to move chromosomes from the center to the cortex. This commonly results in the distribution of an incorrect number of chromosomes to daughter cells, a recipe for chromosomal abnormality. "I first suspected that Fmn2 was related to fertility when Fmn2-deficient homozygous females were successfully mating with wild-type males but not reproducing. There were either no pups being born or litter sizes were 25 percent the normal size," Leader recalled. Reciprocal crosses, which produced normal progeny, confirmed the suspicions and also pinpointed Fmn2 as female-specific. To further investigate the observed subfertility, Leader inspected the uteri of the mice during midgestation. He found a normal number of implantation sites, indicating that a normal number of pups could have been born. "However, we counted a drastically reduced number of normal embryos inside the implantation sites, which means that the embryos were dying during pregnancy. At this point, where Fmn2 was acting was still unclear," explained Leader. A similar formin gene in fruit flies, dubbed cappuccino, had been previously linked to a defect in the ovary. This prompted the team to test whether mutations in Fmn2 would lead to similar defects. Ann Harrington, the team's mouse research specialist who performed the surgeries, recapped the results: "We discovered that healthy ovaries transplanted into Fmn2-deficient females rescued pregnancy loss, whereas Fmn2-deficient ovaries transplanted into healthy females destroyed the healthy females' ability to reproduce." Examination of oocytes from Fmn2-deficient mice during meiotic maturation revealed that the cells were arrested at metaphase I. "The oocytes failed to form a polar body, the cell that signifies completion of the first meiotic division," said co-author Hyunjung Lim, a former HMS postdoc in the lab of senior author Richard Maas, HMS associate professor of medicine at Brigham and Women's Hospital. Whether formin-2 was exerting its influence from inside or outside the cell, perhaps by hormone signaling, had yet to be fully explored. When the researchers injected formin-2 mRNA into an Fmn2-deficient egg cell, they found that it extruded a polar body, suggesting that the protein was acting from inside the cell. Given that Fmn2 has been shown to exist in humans, the discovery of the gene's function in mice lays a foundation to further study human fertility. Leader has recently organized a collaborative investigation to identify mutations in the human Fmn2 in populations of women with certain types of infertility. --Trang Au