Gene Once Thought To Program Ovarian Development Instead Found To Be Critical For Production Of Sperm

January 11, 1999

CHICAGO --- In their quest to decipher -- albeit scientifically -- just what makes women different from men, a group of Northwestern University Medical School researchers made a startling discovery. They found that a gene known as AHC, which had been considered a possible female-specific factor for ovarian development, is actually a prerequisite for male sexual development.

Males lacking the AHC gene have defective testicles and are sterile, while in their female counterparts sexual development and fertility apparently are unaffected. Duplication of the AHC gene causes genetically correct males (that is, having an X and a Y chromosome) to develop the sexual characteristics of females, a phenomenon known as dosage-sensitive sex reversal.

Furthermore, other research indicates that overexpression of the AHC gene may interfere with the function of Sry, a protein produced by the "maleness" gene on Y chromosome that triggers development of the testes, said Northwestern endocrinologist J. Larry Jameson, M.D., who led the study.

These findings suggested a possible role for AHC in ovarian development, he said.

An article on his group's AHC gene research appears in the December issue of Nature Genetics.

Jameson and his research team at the Medical School previously have described the clinical and hormonal features of several patients with mutations in the AHC gene, also known as Dax1. The AHC gene mutation causes adrenal insufficiency, absence of puberty and infertility in boys.

To date, no women have been identified with this condition, probably because of infertility of males with the AHC mutation. Until now, it was impossible to determine the role of AHC in female sexual development.

To study the function of this gene in both females and males, the investigators needed to develop a transgenic mouse model of AHC deficiency. However, producing a mutant AHC mouse proved a significant obstacle, because loss of AHC function in males interferes with normal growth and differentiation of embryonic cells, eventually rendering the mice sterile.

In one of the major achievements of this study, Northwestern researcher Richard N. Yu ultimately generated XY and XX mice that carry the mutant AHC gene through the use of a sophisticated gene excision and recombination technique known as Cre-loxP.

The investigators subsequently found that rather than AHC serving as an ovarian determination gene, loss of its function in females did not impair ovarian development or fertility. Surprisingly, male mice mutant for AHC had defective testicles, which appeared relatively normal at birth but gradually degenerated and resulted in sterility in adulthood.

Jameson said that AHC function might represent one of several factors that cause defects in spermatogenesis and male infertility, perhaps by restricting the inductive activity of testis-promoting factors such as Sry.

In addition, he said, the finding that AHC is not required for ovarian development, in combination with the reported sex-reversal that results from AHC overexpression, supports a role for AHC as an "anti-testis" factor rather than as an ovarian determination gene.

Jameson is the Charles F. Kettering Professor of Endocrinology and Metabolism and chief of endocrinology, metabolism and molecular medicine at Northwestern University Medical School. In addition to Yu, who is a graduate student at the University, Jameson's co-researchers on this study were Masafumi Ito, research assistant professor of medicine at the Medical School, and Thomas L. Saunders and Sally A. Camper of the University of Michigan Medical School, Ann Arbor.
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