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Steroid Surprise

Mutant mystery leads to discovery of new mechanism for hormone transport.
 

"We don’t know what it is yet that’s controlling the movement of these vesicles. ... One of the things we’re doing now is trying to figure out how the steroid gets into the cell.”

Michael O’Connor wasn’t out to revolutionize our understanding of how steroid hormones get around inside organisms. But when mutant fruit fly larvae he was working with mysteriously failed to molt, he knew he had to get to the bottom of it. And at the bottom, it turned out, was a big surprise: Contrary to what’s taught in textbooks, some steroid hormones — a class of chemical messengers found in animals and plants that regulate functions as diverse as immune response and development — don’t just diffuse out of cells. Instead, they’re packed into transport vehicles called vesicles and actively carried across cell membranes.

Ordway professor of developmental biology in the Department of Genetics, Cell Biology and Development, O’Connor studies how steroid hormones do their jobs, starting with being manufactured in and released by one kind of cell and ending with traveling to and altering the activity of other cells at a distance. For years he, like most people in his field, assumed the “being released” part was the simple part of the program: The molecules simply leaked out of their cells of origin and went on their way. Then, one day, he and colleagues Naoki Yamanaka and Guillermo Marqués encountered some surprising results. They were investigating another question — how the brain knows when to trigger cells to produce steroid hormones — when he discovered something puzzling about a mutant fruit fly he had produced in the process. This particular insect was able to produce a steroid hormone known as ecdysone that’s involved in regulating metamorphosis — but the hormone just piled up in cells instead of pouring into the fruit fly equivalent of a bloodstream to travel to target tissues.

“That got us thinking, ‘How do steroids get in and out of cells?’” O’Connor says. A literature search revealed a bit of a scholarly void: Although some previous studies showed that steroids theoretically could move across cell membranes, no one had actually presented conclusive evidence that’s how it really works. So O’Connor and colleagues took a bit of a detour from their research trajectory to look at what was really happening to ecdysone. As reported recently in the journal Cell, they were able to show that this particular steroid gets packed into bubble-like vehicles called vesicles and driven across cell membranes past a calcium-controlled gate rather than simple diffusing out of their cells of origin.

This is basic research, so practical application is not top in the researchers’ minds. But because the findings elucidate mechanisms that can facilitate or impede the ability of steroid hormones to do their jobs, the discovery holds promise for eventual application to everything from designing more environmentally friendly pesticides to reducing the toll of cancer, diabetes and stress-related disorders in humans.

Meanwhile, O’Connor is working to figure out the rest of the story.

“We don’t know what it is yet that’s controlling the movement of these vesicles,” he says. “If you need this transporting mechanism to get it out of cells, then there needs to be some kind of mechanism to take it into the responsive cells. One of the things we’re doing now is trying to figure out how the steroid gets into the cell.”

— Mary Hoff