Park and his colleagues therefore created genetically engineered (“knock-out”) mice lacking the FucM gene. Apart from a slight reduction in body weight, the mice seemed perfectly healthy and were no different in appearance from their normal littermates. But the researchers noticed something unusual when they put the mutant females into mating cages with normal, sexually vigorous males. Typically, the stud will approach a female, touch her body and then sniff her anal-genital region. If the female is receptive, she will invite the male to mount her, by arching her back and raising her hind quarters. But the mutant females actively avoided the advances of the males, suggesting that deletion of the FucM gene had somehow interefered with their sexual and reproductive behaviour.
In mice, sexual behaviour is mediated largely by pheromones secreted in the urine. These chemicals carry sexual signals – they enable the animals to recognize, and motivate them to approach, members of the opposite sex. Normally, females prefer the smell of male urine and vice versa, but females lacking the FucM gene were found to prefer the urine of other females to that of males, spending more time sniffing it when simultaneously presented with both. Their sexual behaviour was similar to that of males, too: they not only rejected the advances of males, but also attempted to mount and mate with other females. Nevertheless, they remained fertile – most became pregnant when forced to mate with a sexually experienced male, and the way they subsequently behaved towards their offspring was no different from normal females.
When the researchers examined the brains of the mutant females, they observed a reduction in the number of dopamine-producing cells in the anteroventral periventricular nucleus (AVPv), a part of the hypothalamus which regulates the release of hormones required for ovulation. The AVPv is known to differ in size between males and females – it is between two to four times larger in females, and contains more cells. It is smaller in females missing the FucM gene, and thus closely resembles that of normal males. The researchers therefore hypothesized that deleting the gene causes changes in brain development that masculinize the brains of the females.
They also speculated that the observed changes occur because deleting the FucM gene perturbs the function of alpha-fetoprotein (AFP). AFP normally protects the female mouse brain from masculinization, by binding to and sequestering the hormone oestrogen during development, and its function is thought to be regulated by the addition and removal of fucose molecules. To test this prediction, the researchers analyzed expression levels of AFP in the mutant females, and the chemical composition of the protein circulating in their bloodstream. This revealed that AFP was present at normal levels, but that there was a significant reduction in the number of AFP molecules that had fucose attached to them.
Other researchers have shown that the neural circuits underlying male behaviours are likely to exist in the normal female mouse brain, and the reverse is probably true. It is also likely that the embryonic human brain has the capacity to differentiate along both the male and female pathways, depending upon exposure to sex hormones during the early stages of development.
These new findings show that FucM is critical for steering the developing mouse brain towards female diffrentiation. But they probably have limited relavence to human sexuality, because although FucM probably plays the same role in humans, it is progesterone, and not oestrogen, that masculinizes the developing human brain. There has been much talk of a “gay gene” in recent years, but no such gene has been discovered, It is, however, only a matter of time before the genes governing human sexual orientation are found.
Park, D., et al. (2010). Male-like sexual behavior of female mouse lacking fucose mutarotase. BMC Genetics 11 (1) DOI: 10.1186/1471-2156-11-62.