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hey may be named ZIG proteins, but they actually prevent the wiring of the nervous system from zig-zagging.

The laboratory of Dr. Oliver Hobert at P&S and a collaborator at Albert Einstein College of Medicine have found a family of six proteins, which they named ZIGs, that maintain the architecture of the nervous system after the developing body has laid down the wiring pattern. The research was published in the Jan. 25 issue of Science.

The finding of these novel proteins, which provide the first glimpse of a mechanism involved in maintaining the proper placement of the "wires" of the nervous system, may some day lead to a better understanding of neurological diseases. But for now, ZIGs are changing neuroscientists' views of nervous system molecular anatomy.

"Neurobiologists often study how the nervous system develops and how nerve cells interact during memory and learning," says Dr. Hobert, assistant professor of biochemistry and molecular biophysics. "Our findings point to the importance of factors, which were previously unidentified, involved in keeping the nervous system structurally intact. More research will elucidate the function of the proteins."

The scientists found the ZIGs in C. elegans, a microscopic worm employed as a model invertebrate to study basic life processes. Since humans also have proteins with similar structures, Dr. Hobert suggests clinicians look at neurological diseases whose causes are either unknown or known to see if analogous ZIG proteins may play a role in the pathology.

Scientists study C. elegans even though it is a primitive organism because it shares enough characteristics of higher organisms to be of value for understanding basic life processes. Its fertilized egg goes through cell divisions that have been well characterized until becoming a 959-celled adult worm. The nervous system consists of approximately 300 neurons, including a brain-like structure in the head; sense organs in the head that respond to taste, smell, temperature, and touch; and dual nerve cords—a major right cord and a minor left cord—that run longitudinally along the ventral side of the animal close to the surface on which the worm wriggles. A nerve cord is a collection of nerve axons, long, tube-like projections of neurons that allow communication among nerve cells or between nerve cells and muscle cells.

The discovery of the maintenance mechanism was a surprise to the research team, which included Dr. Oscar Aurelio, a postdoctoral research fellow in Dr. Hobert's laboratory, and Dr. David H. Hall, a neuroscience professor at Albert Einstein. Dr. Hobert, a developmental neurobiologist, and his colleagues were simply trying to find when and where certain genes would act during C. elegans nervous system development.

They had selected to study from the C. elegans genome 30 proteins, which had never been characterized but had one or more immunoglobulin-like domains. Prior research showed proteins with immunoglobulin-like regions play a role in neuronal development.

A fluorescent dye-based fusion gene system allowed them to watch the expression of their genes-of-choice in the translucent C. elegans as it matured. They attached the promoter region of each of the 30 proteins to a fluorescent dye and created 30 transgenic worms. Transcription factors from the worm's cells regulated the dye's expression, and scientists monitored where in the worm the dye became visible.

They found that six proteins acted in one nerve cell—the PVT cell of the major right nerve cord—after development, after the nervous system had been formed. Dr. Hobert named the proteins ZIG because two in German is zwei (z) and each protein had two immunoglobulin-like regions (ig).

To understand what would happen without the ZIG proteins, they performed microsurgery on the worm and removed its PVT cell. "By ablating the organizer, we affected the structural integrity of other axons," Dr. Hobert says. Axons from the right nerve cord had sections that moved parallel and adjacent to axons in the other nerve cord. They also created a worm missing the zig-4 gene. The mutant worm also revealed similar wiring problems with its axons.

"Without the ZIG proteins the mature nervous system becomes wobbly, with the wiring falling out of place and collapsing onto other wires," Dr. Hobert says.

Before these findings, neurobiologists knew the PVT cell manufactured and secreted a protein, called netrin, that helps guide the formation of the rest of the nervous system. But scientists had been unaware that the PVT cell also plays a role in maintaining the structure of the nervous system.

Dr. Hobert is now studying the effect of deleting the other zig genes. He also has evidence that ZIG proteins are secreted by the PVT cell so he is trying to find their receptors on other nerve cells. Because prior research showed immunglobulin-like proteins often bind to receptors that also have immunoglobulin-like regions, his laboratory is looking for such proteins that have post-embryonic expression profiles that make them good receptor candidates. Additionally, he is using in vitro immunochemical methods to fish out in a soup of ground-up worms those proteins that bind to the zig proteins. Finally, his laboratory is employing the brute force genetic approach. Members of the laboratory will be mutagenizing worms and examining the resulting organisms for a similar phenotype to the zig mutants.

Although Dr. Hobert's laboratory studies C. elegans neurobiology, he believes studies of ZIG proteins from other organisms, such as humans, could be very important. "Many fundamental discoveries in model systems, such as worms and flies, have implications in higher animals," Dr. Hobert says. "It will be interesting to see what might be found if human nerve tissue were tested for zig gene expression."

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