New estrogen receptor found in brains.

Two years ago, graduate student Larry J. Young wouldn't have guessed that his investigation into the sex lives of lizards would lead him to an important region of the rat's brain.

Young and his colleagues at the University of Texas at Austin wanted to understand the role of the hormone estrogen in the sexual behavior of an all-female species of whiptail lizards, Cnemidophorus uniparens (SN: 5/30/87, p.348), and in a related, ancestral species. To do that, he planned to map the distribution of the molecular docking sites, or receptors, for estrogen in lizard tissue.

However, when he tried to develop genetic probes to help him pinpoint these receptors, he wound up with some baffling sequences of nucleotides, the chemical building blocks whose order specifies a protein. Genes typically contain meaningful regions, called exons, with noncoding sequences of nucleotides shoved in between the exons. Messenger RNA molecules, which transfer a gene's information to protein-building machinery, form by matching their nucleotides to the sequences in exons, ignoring the noncoding sections.

The beginning and end of some of the messenger RNA sequences that Young observed matched perfectly the beginning and end of RNA for the human estrogen receptor. But this lizard RNA was missing something in the middle. After much head-scratching, Young figured out that as the lizard RNA formed, it ignored or somehow deleted the information from the fourth exon. Instead it consisted of exons 1 to 3, followed by exon 5.

As a result, says Young, this RNA leads to a newly identified estrogen receptor -- one that exists primarily in the brain.

Knowing that many biomedical researchers wouldn't care much about a new lizard receptor, David Crews, Young's advisor, decided they should find out whether this form of the receptor exists in rats as well. "It would imply evolutionary conservation of this form, which [would] cause us to think that this form would be important," says James K. Skipper, a molecular cell biologist at the University of Texas, who conducted the rat study.

Skipper expected to find the receptor in rat uterine tissue, but instead it represents up to 60 percent of the estrogen receptors found in rat brain tissue, the Texas group reports in the Aug. 1 PROCEEDING OF THE NATIONAL ACADEMY OF SCIENCES. This is the first discovery of a variant of an estrogen receptor in normal tissue, says Skipper.

Other variations of the estrogen receptor exist in cancerous breast tissue, says Bert W. O'Malley of Baylor College of Medicine in Houston. He has found the new variant in rat tumors. "In the area of breast cancer research, it's considered a hot new lead that could have some relevance to the development or progression of tumors," he adds.

The part missing in this RNA specifies a section of the receptor that helps it bind to estrogen. So the researchers don't know whether estrogen can still attach, says Crews.

"Our next step is to do the functional studies and determine whether [the receptor] will bind to DNA," says Skipper.

Ordinarily, when estrogen binds to its receptor, the complex then turns on certain genes. The missing section helps the normal receptor molecule flex, possibly so that the complex can squeeze through the nuclear membrane.

Since this new receptor can't flex, Crews speculates that it may instead work outside the nucleus, in the cell proper. If so, the existence of this receptor may help explain some very rapid reactions the body can have to hormonal changes. These reactions, such as hot flashes or sexual behaviors, occur too quickly to have resulted from the activation of genes. But they could possibly happen if this receptor sets off some faster change in the cell, he adds.