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GENETICS Level-headed Stardust Knows Which Way Is UpPolarity Gene Yields Clues to Organization of Cell Signaling, Structural Growth In 1980, in what might be called the early morning hours of modern genetics, two Heidelberg researchers made a stunning announcement. By making random dings in fruit fly DNA, thereby creating discrete mutations, they had identified 150 genes that control the tiny insect's early embryonic development.
The surface of an epithelial cell resembles the multitiered facade of a building with polarity proteins arranged in bands, one above the other. The stardust protein associates with crumbs as shown above. The scientists Christiane Nüsslein-Volhard and Eric F. Wieschaus, who shared a Nobel Prize for the work, discovered four genes that would later be found to control the intrinsic north-south orientation of embryonic epithelial cells. Mutant versions of the genes produce striking disruptions in the embryo. "It looked like you took a bazooka and just blew it into an embryo--that's what you would get," said Norbert Perrimon, HMS professor of genetics. Other researchers would go on to characterize and clone three of the genes, aptly named bazooka, shotgun, and crumbs. The fourth, stardust, remained an abstraction--until now. Layering the CellWorking with Perrimon, Beth Stronach, HMS research fellow in genetics, has cloned the stardust gene. With colleagues at the University of California, San Francisco, the researchers are beginning to understand how the gene works to set up the basic top-down architecture of the epithelial cells that line the gut, skin, and many other organs of the embryo. Their discoveries, reported in the Dec. 6 Nature, could help researchers answer some of the fundamental questions of biology: how do cells send and receive signals? How do tissues and organs take shape? They could also hold clues to ongoing mysteries such as how cancers arise.
"The cloning of stardust is an important discovery because there are only a few polarity genes known," says Norbert Perrimon, shown here with Beth Stronach. Photo by Pam Murray Until recently, signaling molecules were thought to flit to and from cells in a fairly plebian manner. "Years ago--and this is still the way many people visualize it--signal transduction was thought to be a process by which you secrete a ligand, the ligand finds a receptor, the receptor activates a signaling transduction cascade," said Perrimon. Rarely was mention made of how signals find the right receptor. "People thought those molecules were all randomly distributed and that there was no spatial organization of those signaling complexes," he said. In the late 1990s, a new view arose. Rather than scattered across the surface of the membrane in a haphazard way, receptors were shown to be arranged in a highly organized and predictable manner. Perrimon likens the pattern to the multitiered facade of an office building. He says that some receptors are arranged in bands, one above the other, around the surface of the cell. The receptors, which are produced in the Golgi bodies, ride in vesicles to their appropriate band the way workers take an elevator to the right floor. "If you are a particular signal transduction receptor, you are going to stop at the second floor, and only the second floor," he said. "And that's where all your appropriate signaling partners are going to be directed. It's very, very organized." Researchers went on to show that the polarity proteins crumbs, shotgun, and bazooka each occupy particular bands on the surface of the cell. They speculated that these proteins might be paving the way, essentially preparing the surface to which particular receptors attach. Another Cell Division"We became interested in polarity," Perrimon said, "because we wanted to understand the spatial organization of signaling pathways. We had done all this work with the conception of a unified cell surface, and now we needed to re-evaluate those studies in the context of cell polarity."Working with David Bilder, formerly a research fellow in genetics and currently an assistant professor at the University of California, Berkeley, he set out to identify new polarity genes. The first one they found, called scribble, was a gene with a difference. Bazooka, shotgun, and crumbs produced orderly layers of proteins near the surface of the cell. Scribble's protein product appeared to be providing the scaffold that defined one of the layers. The researchers found that when scribble was mutated, the normal arrangement of polarity proteins, in particular, crumbs, became disrupted as though it could not locate its appropriate tier or, once there, could not hold on to its position. The scribble mutants displayed other anomalies that intrigued Perrimon: their epithelial cells grew in a disorganized and uncontrolled way, much like a cancer. The discovery was not a surprise. To give rise to a tumor, a cell must first become detached from its neighboring cells, which typically share the layered organization and even communicate layer-to-layer across cells. So the cancer cell has to throw off its characteristic polarity. Changing DirectionDepolarization is also involved in normal development and, in particular, morphogenesis, which began to interest Perrimon. "To get cells to do something often requires changing polarity at different stages," he said. To learn more about how depolarization occurs in normal development, Stronach set out in search of a gene on the X chromosome called slipper, which is thought to help initiate normal depolarization.One of the genes she captured fulfilled the structural criteria of the long-sought stardust more than of slipper. To see if it might be stardust, the UCSF researchers expressed the gene, finding that its protein localized adjacent to crumbs. They mutated the captured gene, which caused the severe disruptions in the embryonic cells that had been attributed to stardust more than 20 years before. Other tests corroborated the finding. The addition of stardust to the known constellation of polarity genes opens the door to new research problems. "Our aim now is to understand what those polarity proteins are really doing," Perrimon said. "Why do you need to subdivide the surface of the cell? They are like landmarks, but what is their real function?" The search for answers could lead to a journey as unpredictable as the one that brought Perrimon to ask such questions. "We started with signal transduction," he said. "That led us to polarity. Now most of the lab works on morphogenesis. Let's just say, we are evolving." --Misia Landau |
