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 Cellthat 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.