Gene therapy restores mouse fertility.

Gene therapy restores mouse fertility

A gene deletion causing infertility in mice has been pinpointed and corrected in recent work, illustrating some curious facts about how genes can express themselves in specific tissues. Using a special breed of hypogonadal (hpg) mice, researchers have found that the hereditary form of infertility found in these mice is caused by a deletional mutation of about half of the gene coding for the precursor of gonadotropin-releasing hormone (GnRH) and GnRH-associated peptide (GAP). The peptide pair stimulates the release of key reproductive hormones.

Homozygous mice inherit the hpg gene from both parents and suffer from hypogonadism, characterized by immature sexual behavior, arrested gonadal development and infertility. But scientists at Genentech, Inc., in South San Francisco produced fertile hpg homozygotes by introducing DNA fragments containing the mouse GnRH gene into normal eggs later implanted into surrogate mothers. Subsequent mating of the progeny with hpg mice yielded fertile hpg homozygotes. Hormonal levels and tissue development in these mice were comparable to those in normal mice.

According to researcher Anthony J. Mason of Genentech, the most significant finding was not the successful gene therapy, but the first discovery of neural-specific expression of a gene. Mice that had received the GnRH gene through gene therapy showed a normal number of GnRH-containing neurons in the brain, whereas untreated hpg mice did not. These neurons are part of the hypothalamic-pituitary-gonadal axis essential in maintaining the delicate balance of GnRH release.

Although GnRH and GAP are absent in the brains of untreated hpg mice, an abnormal GnRH messenger RNA (mRNA) is present in the hypothalamic neurons, making the hpg GnRH gene one that is capable of producing specific mRNA but incapable of translating the mRNA information into a protein product.

Others have found similar tissue-specific expression elsewhere. For example, a group at the University of Warwick in Coventry, England, reports in the Nov. 21 CELL that muscle protein genes injected into fertilized eggs of the clawed toad Xenopus borealis are expressed almost wholly in muscles.

Results of the two-year hpg mouse study, which also included scientists from the National Institute of Mental Health in Bethesda, Md., and the University of California at San Francisco, are reported in the Dec. 12 SCIENCE. As Mason told SCIENCE NEWS, there still are unanswered questions. Why does a DNA segment restore functions lost through a deletion nearly three times its length? And why are there gene products found in the liver of the treated animals?

Earlier this year, the Genentech team reported the isolation of the gene for precursors of GnRH and prolactin-release-inhibiting factor in humans and rats. No mutation such as that described in the hpg mouse was found, although there are forms of hypogonadism found in humans. However, there is no direct clinical application of the newly described gene therapy to treating human infertility problems. The technique, called germline gene transplantation, is unacceptable in humans under current biotechnology guidelines (SN: 10/18/86, p.252).

Photo: Micrograph of ovary of a treated hpg female (top) compared with that of an untreated hpg female.