Cell Biology, Plant Biology
University of California, San Diego
Dr. Estelle is a Howard Hughes Medical Institute–Gordon and Betty Moore Foundation investigator. He is also Distinguished Professor and chair, Section of Cell and Developmental Biology at the University of California, San Diego.
In many ways, University of California, San Diego, biologist Mark Estelle is much like the Arabidopsis plants he studies—adaptable and able to shift in whichever direction seems promising for future growth. Unlike animals, whose development is almost completely hardwired from the moment of conception, plants grow and change in response to their environment. That plasticity is precisely what captivated Estelle and has led him to look deeper into the inner workings of plants.
Estelle did his doctoral work on the genetics of hormone regulation in fruit flies but moved from fauna to flora when he saw the opportunity to contribute to a growing field. At the time, not many people were studying plants at the molecular and genetic levels. "Plants do a lot of fascinating things, but we didn't understand much about how they did all of these very cool things. There was a need for a genetic approach," he says.
Estelle chose to bring his training in genetics and hormone biology to the study of the hormone auxin, which drives many of plants' most intriguing behaviors. Unable to seek out an environment of their choosing, plants must alter their growth in response to ever-changing conditions, including light, temperature, water, and nutrient availability. Auxin helps plants respond to these external conditions by controlling organ patterning and development. The hormone helps roots seek water and causes the asymmetric cell elongation that lets stems bend toward sunlight, among other things. But 20 years ago, researchers understood very little about how it worked.
Estelle, applying what he'd learned from flies, began investigating the hormone that underlies so much of a plant's visible plasticity. He began hunting down defective genes in Arabidopsis plants that did not respond to auxin, searching for the molecules that help the hormone transmit its signals. He soon discovered that auxin works by prompting the degradation of proteins that prevent DNA transcription, the first step in producing a protein from a gene. When those regulatory proteins are degraded, the genes they control instantly become accessible and can be expressed again. "That gave us the first clue that protein degradation was really important, and it was the beginning of what's proved to be a long story," he says.
Further pursuit of this line of inquiry led Estelle to solve the decades-old puzzle of how auxin works at a molecular level. He uncovered the auxin receptor and unraveled its mechanism to describe the first receptor found in any organism that uses a small molecule to trigger protein degradation and directly control protein levels—a mode of action that allows for faster, more sophisticated regulation. (Most hormones bind to a receptor on a cell's surface that prompts a cascade of reactions to produce a result only after several signaling steps.) This so-called "F-box" receptor is now known to be an important component in plant cell signaling.
To find out how the receptor detects auxin, Estelle sought the expertise of structural biologist Ning Zheng, now an HHMI investigator at the University of Washington School of Medicine. "I've always felt like it's important not to get too locked into a particular set of tools—I like to be able to think about problems at many different levels," Estelle says. "I can't be an expert at all of them, but I can interact with people doing cell biology and genomics and biochemistry." He and Zheng produced the first structural model of a plant hormone receptor and revealed that when auxin fills a cavity in the receptor's surface, the receptor becomes able to bind the proteins whose degradation initiates plant growth.
While Estelle's work has paved the way to a new understanding of plant hormones, a lot remains to be learned. He now wants to understand the downstream pathways that auxin activates, which can vary according to tissue and cell type. He plans to begin by dissecting the signals and natural variations that drive the growth of seedling stems called cotyledons. Estelle hopes that by studying their hormone- and temperature-related growth, and the genetics that drive that growth, he can begin to comprehend the complex network of hormonal signaling. "These are very complex processes. We have the tools to identify all the different genes involved, and the challenge is to figure out how all the different functions fit together in a network that's capable of responding to all the different stimuli that it encounters," he says. "It's incredibly beautiful that it is so complex. If it were simple, we'd have it figured out and it would be boring."