April 14, 2005

Of Mice and Men’s (and Women’s) Contraceptives:
Study of Unique Reproductive-Cell Protein in Mice
Could Lead to New Contraceptives for Women and Men

(Philadelphia, PA) - Mice lacking a special protein found only in germ-line cells results in infertility in both males and females, according to a new study from researchers at the University of Pennsylvania School of Medicine. Norman Hecht, PhD, Professor of Human Reproduction in Penn’s Center for Research in Reproduction and Women’s Health, and colleagues say that these investigations point the way to a new type of contraceptive for both men and women. They report their findings in this week’s online edition of the Proceedings of the National Academy of Sciences.

“Not many proteins are expressed in both male and female germ lines that are specific only to the germ line,” says Hecht. Germ line refers to the group of cells that give rise to either sperm or eggs in animals, as opposed to all other cell types, which are called somatic cells. “There are many proteins whose deletion will cause male infertility, and others for creating female infertility, but not many that will lead to both male and female infertility without affecting the somatic cells.”

Animals deficient in the protein - called MSY2 - are infertile, but are otherwise healthy and completely normal. Male mice produce no functional sperm, and females show early loss of eggs and defects in ovulation.

The MSY2 protein is part of a family of proteins, called Y-box proteins, that are present in most organisms, ranging from bacteria to humans. In the nuclei of developing germ cells, MSY2 enhances synthesis of a select group of messenger RNA (mRNA) molecules and transports them from the nucleus into the cytoplasm. There, MSY2 proteins stabilize the mRNAs, which are used to make new proteins. Many of these proteins are critical for the production of normal sperm and also are unique to germ cells.

“When trying to develop a new contraceptive, it’s hard because we need to identify a target that’s specific to the germ cells,” says Hecht. “Clearly, if we inactivate the function of a protein with a small inhibitory molecule, it can’t be a protein also active in such somatic tissues as brain, heart, liver, and so forth, only in the reproductive cells we want to target.” Investigating germ cell molecules for contraception is also desirable because it frequently allows reversibility.

Hecht and colleagues have been proposing this scheme for the last several years, but how does the absence of the MSY2 protein result in male and female infertility? “We don't know the complete mechanism yet, but it may be preventing the stabilization of specific messenger RNAs that need to be used at specific times as germ cells differentiate into mature sperm and eggs,” explains Hecht. “An equally likely possibility is that the absence of MSY2 disrupts the timing of how specific mRNAs are used during germ cell differentiation. As cells become mature sperm, there’s a precise order of synthesis of many essential proteins needed to create functional gametes. We think the absence of the MSY2 protein causes problems in the timing of sperm or egg development. We’re working hard on understanding this mechanism.”

A similar human equivalent of MSY2, Contrin, has been identified by the research group and their studies indicate it is also a germ cell-specific protein. Using MSY2 as a mouse model, Hecht and colleagues hope that Contrin can be developed as a new non-hormonal target for human contraception.

The study was funded by the National Institutes of Health. Juxiang Yang, Sergey Medvedev, Junying Yu, and Richard M. Schultz from Penn, and Linda C. Tang, Julio E. Agno, and Martin M. Matzuk from Baylor College of Medicine (Houston, TX) are study co-authors. The authors report no conflicts of interest related to this research.

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