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| |  Molecules That Guide Nerve Growth May Help Repair Damaged Spinal Nerves SAN FRANCISCO -- April 25, 1997 -- Nerve repair after major spinal cord injury has long been regarded as impossible, but current scientific discoveries from animal studies on how nerve cells form connections properly during development suggest that there may be a real possibility of one day reversing paralysis. In the April 24 issue of the journal Nature, developmental biologists with the Howard Hughes Medical Institute at the University of California San Francisco, and their collaborators at the Whitehead Institute for Biomedical Research in Boston and at the Jackson Laboratory in Bar Harbor, Maine, report the discovery of molecules that help guide nerve-cell connections in the spinal cords of embryonic rats. Their finding indicates that these or similar molecules may one day aid in guiding nerve repair in human spinal cords, the researchers say. According to Marc Tessier-Lavigne, associate professor of anatomy and HHMI investigator at UCSF, "Guidance molecules similar to the ones we have identified are likely to prove useful in developing treatment strategies for restoring lost functions in humans with spinal cord injuries." A precedent for using naturally occurring growth-influencing molecules in difficult-to-treat neurological disorders has already been established. Growth factors earlier discovered to be important for embryonic brain development now are being investigated as experimental treatments for Parkinson's disease and for Lou Gehrig's disease, for example. A severed finger may be sutured back on and sometimes regain movement and sensation during recovery. However, severed connections in the spinal cord -- which relays messages between the body and the brain -- do not regenerate much at all, Tessier-Lavigne explains. Quadriplegics and paraplegics do not regain the function of their paralyzed limbs. Part of the reason for this failure may be the presence of recently discovered molecules in the adult spinal cord that can inhibit the growth of nerve fibers. But researchers also have identified several potential growth factors. These growth factors might spur growth of new spinal nerve cell connections if the inhibitors could somehow be disabled, Tessier-Lavigne says. "To obtain repair of severed nerve connections in the spinal cord it will be necessary to block the inhibitory molecules," Tessier-Lavigne says. "It also will be necessary to supply growth factors that will stimulate the sprouting of new growth fibers." "But spinal nerve repair will require that nerve cells restore function and not act as crossed wires that do no good or that cause additional damage," he adds. "Growth-guiding molecules could be used to achieve orderly nerve-cell re-connections." Three years ago, Tessier-Lavigne and colleagues discovered two members of a previously unknown class of growth-guiding molecules, which Tessier-Lavigne named "netrins," from the Sanskrit word meaning "guide." Netrins are needed to form accurate connections between nerve cells that transmit sensory signals through the spinal cord. The netrins can either attract or repel growing nerve fibers, Tessier-Lavigne says. Tessier-Lavigne's research group and its collaborators now report the discovery of molecules that are netrins' partners in growth guidance. In the case where the partners attract, these "receptor" molecules, located on the branching nerve cell, are needed to direct the growth of new nerve fibers toward increasing concentrations of netrin within the spinal cord. The directional growth results when netrin molecules diffuse away from their source, drifting toward the branching nerve cell, where they attach to the netrin-receptor molecules on the cell's surface. The attachment stimulates the branching fiber to grow toward the netrin source and to form a proper connection with another nerve cell. One of the receptors now implicated directly in nerve guidance is called DCC, for "deleted in colon cancer," because loss of part of the human chromosome containing DCC was suspected to play a role in cancer. Tessier-Lavigne became interested in DCC after researchers probing a previously suspected netrin receptor gene in the simple, speck-sized roundworm, C. elegans, an easy-to-study animal "model" popular with developmental biologists, found that it was related to DCC. This prompted Tessier-Lavigne and his colleagues to test the possibility that DCC is a netrin receptor in mammals. The demonstration by these researchers that DCC can function as a netrin receptor in a simplified tissue culture model was published last October in the journal Cell. The research reported today in Nature extends these observations from tissue culture to living animals. In a collaborative study of mice lacking the DCC gene, led by Amin Fazeli, a graduate student in the laboratory of Robert Weinberg, PhD, a professor at the Whitehead Institute for Biomedical Research in Boston, the researchers found no increased incidence of cancer. However, the researchers did find that sensory nerve cells formed abnormal connections in the spinal cords of DCC-deficient mice. This led the researchers to conclude that DCC is in fact an important netrin receptor in mice, and probably in humans and in other vertebrates as well. In a separate paper appearing in the same issue of Nature, Tessier-Lavigne's lab team reports the identification of two additional netrin receptors in rats, also tracked down thanks to the earlier identification of similar genes in C. elegans. It is still not certain whether these receptors guide attraction or repulsion to a netrin source, according to Tessier-Lavigne. The discovery of the growth-guiding interplay between netrins and their receptors occurs an entire century after the existence of these molecules -- chemical attractants acting at long range --was first postulated by a giant in the field of neuroanatomy, Santiago Ramon y Cajal, an early Nobel laureate. In addition to the Whitehead Institute collaborators, additional contributors to the research reported in Nature are HHMI and UCSF graduate student E. David Leonardo, and postdoctoral fellows Lindsay Hinck, Masayuki Masu and Kazuko Keino-Masu; and Susan L. Ackerman, a research scientist of the Jackson Laboratory, in Bar Harbor, Maine. Major funding for the research was provided by the International Spinal Research Trust, the American Paralysis Association, the Howard Hughes Medical Institute and the National Institutes of Health.
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