January 6, 1999
La Jolla, CA – Like a sextant that helps guide ships at sea, a specific combination of genes has been identified that directs newly born nerve cells to their final destinations in developing organisms.
Embryonic nerves must pick their pathways in a specific and ordered manner, and investigators led by John Thomas, an associate professor at The Salk Institute for Biological Studies, have deciphered the first combinatorial code that spells out one of these pathways.
The results, published in the January 7 issue of the journal Nature, “provide a clear demonstration that a specific combination of genes determines the pathways along which developing nerve cells will grow,” said Thomas, senior author of the study, adding that neuroscientists long suspected such a code might exist but “direct evidence was lacking.”
The scientists examined two sets of nerve cells that grow from the central nervous system outward to abdominal muscles in the fruit fly Drosophila. Once there, these cells, called motor neurons, form connections that will allow them to control movements in the mature animal.
One class of neurons, known as ISNb cells, innervate a specific subset of muscles; the other, ISNd neurons, grow toward a different set of muscles. By switching the expression of a single gene, the Salk team was able to switch the growth pattern and identity of these neurons.
Both ISNb and ISNd motor neurons express a gene called islet, but a similar gene called lim3 is active only in ISNb neurons. When Thomas and his colleagues forced lim3 to turn on in ISNd cells, the neurons abandoned their normal track and instead grew toward the muscles normally targeted by ISNb cells. Conversely, when the investigators blocked lim3, the ISNb cells behaved like ISNd neurons, and when both islet and lim3 are eliminated, the cells became totally confused and never reach the abdominal area.
“It appears that a host of genes determines that a cell will be first a nerve cell, second a motor neuron, and third a particular type of motor neuron in terms of which muscles it will grow toward,” said Thomas.
“Lim3 and islet constitute a code that instructs nerve cells to travel to specific destinations.”
Identifying the genes that guide neurons to their targets is critical to nerve regeneration efforts that scientists hope will eventually be used to treat neurodegenerative diseases, including Alzheimer’s, paralysis due to spinal cord injury and congenital conditions such as blindness and mental retardation. And because islet and lim3 have analogs in vertebrate organisms that appear to be active in similar patterns to those seen in flies, the investigators believe their work will help pave the way to understanding how nerve growth is regulated in higher organisms.
“Clearly, we’re still a long way from being able to reconstitute a nervous system or even part of one,” said Thomas. “But knowing how cells get where they’re supposed to be is a key piece of the puzzle.”
First author of the study is Stefan Thor, currently at Harvard Medical School and formerly a postdoctoral fellow in Thomas’s laboratory. The study was done in collaboration with Siv G. E. Andersson and Andrew Tomlinson at the College of Physicians and Surgeons of Columbia University. The work was supported by the National Institutes of Health, a Pew Scholars Award to Thomas, an EMBO Long-term Fellowship to Andersson and a HFSP Long-term Fellowship to Thor.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.