By David N. Leff

Every now and then, a patient sues the surgeon who left an instrument or gauze pad behind in the wound.

Nature is also culpable in similar malpractice when, albeit rarely, a baby is born with two complete sets of internal sex organs, one male, one female.

An article in today's Nature, dated Oct. 15, 1998, reports how this embryogenic slip-up can happen. It's titled: "Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a."

The paper's senior author is developmental geneticist Andrew McMahon, a professor of molecular and cellular biology at Harvard University, in Cambridge, Mass.

"Basically, males and females are bipotential to start with," he told Bioworld Today. "Early in embryogenesis, they have the sex ducts that would make either the male or the female reproductive system. And what's required is that in the female they specifically do not have the hormonal factors that support male development. Testosterone is such a factor. And that they fail to produce an inhibitor, which leads to the loss of the female duct. " This inhibitor is called MIS, standing for "Mullerian inhibiting substance."

In a proto-female embryo, Mullerian ducts develop into oviduct, uterus, cervix and upper vagina. But in a wannabe male, the testes produce Mullerian-inhibiting substance (MIS), which makes those ducts abort their job of feminization.

They also make testosterone, which takes on production of the maleness acoutrements — epididymis, vas deferens and seminal vesicles, as well as the penis.

As for the Wnt-7a gene, the theme of his Nature paper, McMahon explained: "Its action determines the response to this MIS hormone. That key gene is expressed in both the male and female reproductive systems. And it's signaling to the underlying progenitor cells to differentiate and start organizing the female structures of reproduction."

He added, "In both the males and the females, one of the steps of differentiation is to activate the receptor that responds to MIS. That leads to a specific consequence. The female has no consequence. Although that receptor is produced, she doesn't make MIS because she doesn't have the testis. But the male requires production of that MIS receptor to be able to trigger the loss of the female reproductive system.

"So what happens in the male when the Wnt-7a gene is knocked out — as in our male mice — the female reproductive component, rather than being lost, persists. And that persistence basically screws up the plumbing.

Two Genders In One — Not Common

"These pseudohermaphrodites have the normal Y-chromosome maleness component," McMahon said, "and they produce testosterone and all that stuff. I believe they are potent, but not fertile. That's largely a plumbing problem, because the presence of both female and male reproductive systems leads to sperm backing up into the female duct, instead of passing out through the male urethra. This happens because both tubes open at the same position, which leads to mis-routing of sperm.

"That," he added, "is the feminization syndrome. But it's not one that you would notice by looking at the individual. You'd only see it if a person presented himself as being infertile. And then one performs some analysis, to find that he had two reproductive systems, one male, one female. It's probably not a common problem."

As if with political correctitude, McMahon has another research paper pending publication, which documents that "a Wnt factor is also required in females to suppress male development."

He reiterated that "the Wnt-7a gene is required for the normal function of the female reproductive system. So in its absence — as in our female knockout mice — that system doesn't make, for example, uterine glands, which are required to support normal uterine development of the embryo. So if one in principle inhibited Wnt-7a signaling in an adult, that should lead to inability to support pregnancy."

He said that such temporary inhibition of this pathway "may be a target for contraceptive action," and added that infertility also might be a therapeutic target.

"I suspect that in the future," he said, "people will find a subgroup of patients who have both male and female reproductive systems, due to a lack of Wnt-7a. In such cases," he added, "surgical intervention would probably be conceivable" [no pun intended].

"Surgical removal of this redundant other-sex component, if it did occur in humans, would likely be fairly simple," McMahon said. "You're not excising a huge amount of tissue, only a rather simple tube that might be causing the problem."

Managing The Dorsal-Ventral Connection

Taking care of the sex side of embryonic life isn't the only role played by Wnt-7a in prenatal development. In fact, McMahon and his co-authors encountered this gender aspect while scoping the gene's day job — sorting out the tops and bottoms of mammalian limbs.

"We know that Wnt-7a has an important role in regulating dorsal-ventral polarity in the limb," McMahon noted, "and we've focused mostly on that component of development.

"The back of your hand," he noted, "is dorsal, and the palm is ventral. If you bend your fingers, they bend only one way, towards the palm. And all of that is dependant upon a unique hooking up of muscles, tendons and nerves. That distinguishes bottom from top, and the process is regulated by this same Wnt-7a signal. It's a dorsal signal, and without it the hand develops as if it's ventral, so basically all the ventral components are duplicated on the dorsal side.

"As yet, nobody's seen this syndrome in humans." McMahon said. "When we got this data, I contacted a bunch of clinicians, and asked if they had seen any patients who presented with two features that should be very diagnostic: One, they're infertile; two, they have abnormal jointing of their hands. And they should otherwise be perfectly healthy. Nobody could tell me that they had seen such people." *

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