Gene mutation that steers nerve cells off course identified

Scientists at the Salk Institute for Biological Studies have identified a gene mutation in mice that causes growing neurons to lose direction after they have left the spinal cord.

Washington, November 24 : Scientists at the Salk Institute for Biological Studies have identified a gene mutation in mice that causes growing neurons to lose direction after they have left the spinal cord.

The researchers have named the mutation Magellan, after the Portuguese mariner whose ship Victoria was first to circumnavigate the globe.

Lead researcher Dr. Samuel Pfaff, a professor in the Gene Expression Laboratory, says that this mutation occurs in a gene that normally guides motor neurons-the nascent cells that extend from the spinal cord and find their way down the length of limbs such as arms, wings and legs-on the correct course employing a newly discovered mechanism.

He says that when growing neurons lose direction as a result of the mutation, the elongating cells may develop "kinks", fold back on themselves or become entwined in a spiral to form coils outside the spinal cord.

"They appear to become lost in a traffic roundabout," described Pfaff, who observed the growing neurons with fluorescent technology.

The researchers believe that understanding how motor neurons reach the appropriate targets may help implement novel therapies, including embryonic stem cell replacement, for the treatment of presently incurable disorders such as Lou Gehrig's disease, in which motor neurons undergo irreversible decay.

"Embryonic studies provide useful insights on how to replicate the system in an adult," said Pfaff.

He also pointed out that the mechanisms used by motor neurons are likely to be similar to those used in other parts of the central nervous system, such as the brain.

Though the Magellan mutation has been found in mice, the affected gene called Phr1 has also been identified in other model systems like fruit flies and the worm species C. elegans.

A growing nerve bears at its bow a structure called the growth cone, a region rich in the receptor molecules whose job is to receive cues from the environment. During development, the growth cone continuously pushes forward, while the lengthening neuron behind it matures into the part of the cell called the axon.

When the growing cell "lands" at its target in a muscle cell, the axon will relay the messages that allow an animal to control and move its limbs at will.

Pfaff's team discovered that in Magellan mutants, the growth cone becomes disordered, and instead of forming a distinct "cap" on the developing neuron, the cone is dispersed in pieces along both the forward end and the axon extending behind it.

He said that without the correct orientation of receptors, signals could not be read accurately, resulting in growth going off course.

"A precise gradient normally exists across the cone, which is disrupted in the Magellan mutants," said Pfaff, adding that cells lose their polarity as a result of it.

Since the polarity is a universal feature common to all growing neurons, he said: "Phr1 is likely to play a role in most growing neurons to ensure their structure is retained at the same time they are growing larger."

The study has been reported in the journal Neuron.

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