Johns Hopkins researchers report that once a growing nerve "tastes" a certain protein, it loses its "appetite" for other proteins and follows the tasty crumbs to reach its final destination. The finding in mice, reported in the July 23 issue of Cell, appears to help explain how nerves connect to their targets and stop growing once there, a process important for the normal development of mouse and man.
During prenatal development, a nerve connects to its proper targets in part by obeying protein signals sampled en route. If the signals aren't right or aren't found, the growing nerve can connect to the wrong organ or not connect at all.
In experiments on mice, the Hopkins scientists learned that a protein called NT-3 (neurotrophin-3), produced and distributed at the halfway point, and one called NGF (nerve growth factor), which is expressed at the target organ, both attract the growing ends of a certain type of nerve cell. However, the Hopkins team found that only NGF can convince the nerve that it "tastes better," an ability that allows the nerve to leave the halfway point, grow to the source of NGF and then stay put.
"It seems incredible that a nerve finds its target this way during development, but we have a new glimpse into exactly how it happens," says David Ginty, Ph.D., associate professor in the Department of Neuroscience of Hopkins' Institute for Basic Biomedical Sciences and a Howard Hughes Medical Institute investigator. "We have found that the growth of some nerves is controlled by target-derived cues, which are proteins that chemically change the nerves so that they are enticed to leave intermediate targets for final targets."
Scientists have long known that mammals, including mice and humans, normally grow more nerve cells than are needed during development, and that those that don't successfully connect die off. Nerve cells have a long way to travel, and they are attracted to a number of intermediate sites along the way. But scientists haven't understood exactly how the nerve endings move on.
Using mice engineered to lack either NT-3 or NGF, the Hopkins scientists, led by postdoctoral fellow Rejji Kuruvilla, Ph.D., and graduate students Larry Zweifel and Natalia Glebova, examined the nerve connections to a number of internal organs, including the heart, small intestine, salivary glands and fat deposits.
In mice without NT-3, nerves failed to grow to intermediate targets. In contrast, nerves in mice lacking NGF stayed at the intermediate site; they failed to grow into the final targets. Therefore, it appears the nerves need to first taste NT-3 and then NGF to properly connect to their targets, the researchers say.
To discover why nerves prefer NGF even when they can taste NT-3, the scientists compared nerve growth in the genetically engineered mice to growth in normal mice. Through these experiments, the researchers discovered that after they taste NT-3 and follow it to the intermediate site, growing nerves detect and "swallow" a small amount of NGF, wafted from the final target.
The key to the nerves' preference, however, is what happens next. The NGF then is transported to the nerve cell's command center, where it causes production of another protein. This protein, p75, moves back to the nerve's growing tip and makes it impossible for NT-3 to act. Now less sensitive to NT-3, the nerve's tip snakes through clouds of increasing amounts of NGF toward the organ producing the NGF. Once there, it stops.
"We were pleasantly surprised to discover that the ultimate target expresses a protein that physically changes the approaching nerve cell and makes other growth protein 'competitors' seem less appealing," says Ginty. "We suspect that other nerve cells may be manipulated in a similar fashion by a different series of proteins. We'll be studying that next."
The research was supported by grants from the National Institutes of Health and by the NIH Medical Scientist Training Program. Authors on the paper are Johns Hopkins researchers Kuruvilla, Zweifel, Glebova, Bonnie Lonze, Haihong Ye and Ginty, along with Gregorio Valdez from the State University of New York at Stony Brook.
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