Biologists find molecule that guides axons

A receptor implicated in Down syndrome and fruit fly development also charts a path for nerve fibers.

Like a complex electronic device, the “wiring” of the nervous system has no tolerance for error. As an embryo develops, wirelike axons sprout from cells, elongating to form networks of neurons in the brain and spinal cord. Some axons cross the body from one side to the other, while others stay put. Neuroscientists have long wondered how axons migrate to form trillions of connections among neurons. How do they know where to travel and when to cross? Molecular signals are at the heart of the puzzle.

The first such signal, a guidance molecule called netrin-1, was identified about 20 years ago. Since then, researchers have found receptors on the axons that help them steer toward their targets. Now Yale researchers have found another molecule that guides axons on their intricate journey.

A team led by Elke Stein, Ph.D., assistant professor of molecular, cellular and developmental biology and of cell biology, reported in June in the journal Cell that it had discovered that a gene linked to mental retardation in Down syndrome is also essential for axons in the spinal cord to cross from one side of the body to the other.

The protein made from that gene is a receptor called DSCAM, which stands for Down Syndrome Cell Adhesion Molecule. DSCAM is already familiar to researchers. Its genetic instructions are on chromosome 21, and people with Down syndrome have three copies of the chromosome rather than the normal two.

The Yale scientists found DSCAM through studies of nerve fibers called commissural axons that cross at the midline of the spinal cord, which divides the body into its right and left halves. Cells at the midline instruct axons by secreting attractive and repulsive molecules. Netrin-1, the guidance molecule identified 20 years ago, is one such molecule. It attracts and guides commissural axons over long distances to the midline of the central nervous system. Researchers had previously found that netrin-1 signals DCC, a receptor that steers commissural axons to their targets. But they noted that some axons migrate even when DCC is absent. There had to be another receptor involved, and scientists searched for it for more than 10 years.

The missing receptor, Stein’s lab found, was DSCAM, which was known to regulate nervous system development in fruit flies. But in humans it had only been known to help neural cells adhere to each other, and was thought to contribute to mental retardation in people with Down syndrome. In collaboration with scientists from Genentech, Stein and graduate student Alice Ly found that DSCAM at the tips of migrating axons is required in order to cross the midline in response to the attractant, netrin-1, which activates DSCAM and initiates directional growth of commissural axons in much the same way that a key turns the ignition and starts a car.

The researchers showed that commissural axons that lack DSCAM lose their “sense of direction,” fail to grow and don’t reach the midline. The Stein laboratory is now investigating whether DSCAM plays a key role in wiring other parts of the nervous system and its contributions to mental retardation in Down syndrome.

—Jenny Blair

Bacteria disable immune cells by exploiting a genetic similarity

The bacteria that cause Legionnaires’ disease and Q fever, both of which are linked to pneumonia, use a clever form of mimicry to survive inside host cells, according to a team of Yale scientists. Both bacteria use genes that have evolved in tandem with genes in their hosts and that disarm the immune system cells that are trying to kill them, the researchers reported in the journal Science in June.

“Because of their lifestyle, trying to identify how these organisms cause disease has been really difficult,” said Craig R. Roy, Ph.D., associate professor of microbial pathogenesis, referring to the fact that the bacteria live inside their host cells. Roy’s team knew that some disease-causing bacteria inject proteins into human cells. What those proteins are and what they do, though, was unknown.

Previous research on the genomes of the bacteria, Legionella and Coxiella, had turned up many genes with areas called ANKs (ankyrin repeat homology domains). These genes bear a strong resemblance to important genes in eukaryotic cells, those cells with a nucleus that are found in humans and other advanced life forms. Legionella and Coxiella appear to have “hijacked” genes from their hosts in order to survive in the cell. In fact, some species of these bacteria cannot exist outside a eukaryotic cell.

Roy’s lab showed that ANK proteins are secreted into macrophages—immune system cells—and once inside, the proteins turn off mechanisms designed to destroy the bacteria. The macrophage ordinarily kills bacteria by exposing them to a destructive acidic environment, but the ANK proteins prevent the acidic compartment from being transported to the bacteria by mimicking a natural process that occurs during cell division.

Roy believes that more such survival tricks of gram-negative pathogens will be found, and that the diseases may one day be preventable with a vaccine that disables the ANK protein and allows macrophages to complete the job of destruction. “This study at least gives us a foothold,” he said.

—J.B.

et cetera

Metastasis and a hybrid cell

Metastasis, the spread of cancer throughout the body, may be caused by a hybrid cell that takes on the most dangerous features of two different cell types, according to a review by Yale scientists in the May issue of Nature Reviews Cancer.

According to dermatology researchers John M. Pawelek, Ph.D., and Ashok K. Chakraborty, Ph.D., the natural hybrids take on both the white cell’s migratory ability and the cancer cell’s tendency to divide uncontrollably. The hybrid can travel to other organs and seed new cancer sites.

“This is a unifying explanation for metastasis,” said Pawelek. “We expect this to open new areas for therapy based on the fusion process itself.” So far, one case of fusion in humans and many cases in mice have been reported. Pawelek said more research is needed to be certain that fusion accounts for metastasis in humans.

—J.B.

A clue to evolution

After 16 years of research, Yale scientists have produced the first images of a group II intron, a cellular molecule whose ancestor may have opened the door to the evolution of higher organisms.

Anna Marie Pyle, Ph.D., professor of molecular biophysics and biochemistry, and her team crystallized the intron of a salt-tolerant bacterium that lives in the Sea of Japan. High-resolution images of the crystal, which appeared in Science in April, support the hypothesis that the intron shares a close evolutionary heritage with the human spliceosome, a complex molecular machine found in higher organisms that allows many proteins to be made from one stretch of the genome.

“The molecules showed us their structure, their active site and their activity,” said Pyle. “We were even able to visualize their associated ions.” Pyle hopes the introns may be developed into agents for gene therapy.

—J.B.


			Originally published in Yale Medicine, Autumn 2008. Copyright © 2008 Yale University School of Medicine. All rights reserved.