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Researchers at Columbia University College of Physicians & Surgeons and the Albert Einstein College of Medicine have found, for the first time, that certain proteins maintain the nervous system architecture after the developing body lays down the wiring pattern. The finding may someday lead to a better understanding of some neurological diseases but, for now, is changing neuroscientists' fundamental understanding of nervous system anatomy.

The investigators, led by Dr. Oliver Hobert, P&S assistant professor of biochemistry and molecular biophysics, have identified a family of six proteins, called ZIGs, responsible for keeping the wiring of the nervous system in its proper place in the mature organism. The results will be published in the Jan. 25 issue of Science.

Although the researchers identified the proteins in C. elegans, a microscopic worm employed as a model invertebrate to study neurobiology, humans have proteins with similar structures. "Clinicians should now look at neurological diseases whose causes are unknown or even those that are known and see if analogous human ZIG proteins may be playing a role in the pathology," Dr. Hobert says.

Scientists study C. elegans even though it is a primitive organism because it shares enough characteristics of human biology 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, 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, and other nerves. A nerve cord is a collection of nerve axons, long projections of neurons that allow communication between nerve cells or between nerve cells and muscle cells.

The discovery of the maintenance mechanism was a surprise to the research team. Dr. Hobert, a developmental neurobiologist, and his colleagues had not set out to find these maintenance proteins. The team had been studying when and where certain genes would act during the development of the C. elegans nervous system.

But in the group's search, they found that six ZIG proteins started acting in one nerve cell—the PVT cell of the major right nerve cord—after development, after the nervous system had been formed. "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 had known the PVT cell of the major right nerve cord manufactured and secreted a protein, called netrin, to help guide the formation of the rest of the nervous system but were unaware the PVT cell also played a role in maintaining the structure of the nervous system.

The PVT cell makes and then discharges the ZIG proteins outside of the cells to act on other nerve cells. Dr. Hobert and his collaborators are now trying to understand how the proteins interact with the other nerve cells to help them stay in their proper place.

"Neurobiologists often study how the nervous system develops and how nerve cells interact during memory and learning," Dr Hobert says. "Our findings point to the importance of factors, previously unidentified, involved in keeping the anatomy of the nervous system intact. More research will elucidate the proteins functions."

Dr. Hobert named the proteins ZIG for two reasons: Each protein has two immunoglobulin-like, or ig, regions. The "z" comes from zwei, the German word for two.

Dr. Oscar Aurelio, a postdoctoral research fellow in Dr. Hobert's laboratory, and Dr. David H. Hall, professor in the department of neuroscience at Albert Einstein College of Medicine, participated in this study.

The research was funded by grants from the March of Dimes Foundation, the Whitehall foundation, the Searle Foundation and a NIH postdoctoral fellowship for Dr. Aurelio.