Mollusk gene rewrites history of sex hormone.

Evolutionary biologists have found that the California sea hare, a mollusk that goes by the scientific name of Aplysia californica, has a protein similar to proteins in people that respond to estrogen and other steroid hormones. The surprising finding suggests that estrogen was the first such hormone to evolve and that the estrogen-signaling system dates back more than 600 million years. Contrary to past thinking, the estrogen system apparently evolved before the divergence of invertebrates, such as mollusks and insects, and vertebrates, such as fish and mammals. The hormone-binding proteins known as steroid receptors, "had never been found outside the vertebrates," says Joseph Thornton of the University of Oregon in Eugene, who led the work. "Everyone assumed they emerged somewhere deep in the vertebrate lineage."

Estrogen, testosterone, and progesterone are the most familiar of the steroids. All these hormones bind to receptors in cells and thus turn on sets of genes that determine differences between the sexes, regulate reproduction, or guide other aspects of physiology and behavior. People and other vertebrates have genes for six steroid receptors, including two estrogen receptors.

Since estrogen is created from other steroids, scientists once assumed that its receptors arose after the other hormone receptors were in place. Two years ago, however, Thornton and his colleagues found a gene for an estrogen receptor in a lamprey, one of the most primitive vertebrates. They proposed that estrogen was the original sex hormone and that one of its receptors was the first to evolve (SN: 8/11/01, p. 94).

Thornton, his Oregon colleague Eleanor Need, and David Crews of the University of Texas at Austin have now probed the DNA of A. californica for genes similar to those for vertebrate estrogen receptors. One such gene is active in the neural and reproductive tissues of the mollusk, they report in the Sept. 19 Science.

Steroid receptors and related receptors are "probably more ancient and widespread than previously believed," says Vincent LaudeT of Ecole Normale Superieure in Lyon, France.

The new report "will cause all of us to rethink our models on the evolution of steroid-hormone signaling," adds Michael Baker of the University of California, San Diego.

Unexpectedly, the receptor encoded by the sea hare's newfound gene isn't responsive to estrogen, Thornton and his colleagues discovered.

Guided by known vertebrate steroid receptors and the new mollusk receptor, the team then deduced a probable amino acid sequence for the ancestral protein in both vertebrates and invertebrates. The researchers synthesized that protein and found that it responds strongly to estrogen and only weakly to other steroids. Thornton concludes that the original protein was estrogen sensitive and that in certain animals, such as the sea hare, its activity is no longer regulated by the hormone.

Bert O'Malley of Baylor College of Medicine in Houston argues that it's more likely that the ancestral receptor was unresponsive to steroid hormones and only later came under the influence of estrogen in certain animals. Laudet shares that view, noting that he's unconvinced that the amino acid sequence deduced by Thornton is the correct one for the ancestral receptor.

Given the new finding, Thornton calls for more attention to the impact of hormone-like pollutants, so-called endocrine disruptors (SN: 3/1/97 p. S19), on animals other than vertebrates. "I think it's very important from an ecological perspective that our policies and our testing programs broaden their scope to include the full range of organisms that could be affected," he says.