Newly launched nerve cells in a growing embryo must chart their course to distant destinations, and many of the means they use to navigate have yet to surface.
In a study published in the current issue of the journal Neuron, scientists at the Salk Institute for Biological Studies have recovered a key signal that guides motor neurons – the nascent cells that extend from the spinal cord and must find their way down the length of limbs such as arms, wings and legs.
The Salk study, led by Samuel Pfaff, Ph.D, a professor in the Gene Expression Laboratory, identifies a mutation they christened Magellan, after the Portuguese mariner whose ship Victoria was first to circumnavigate the globe. The Magellan mutation occurs in a gene that normally pilots motor neurons on the correct course employing a newly discovered mechanism, their results demonstrate.
In the mutants, growing neurons can be seen leaving the spinal cord normally but then appear to lose direction. The elongating cells develop “kinks” and sometimes fold back on themselves or become entwined in a spiral, forming coils outside the spinal cord. “They appear to become lost in a traffic roundabout,” described Pfaff, who observed the growing neurons with fluorescent technology.
Understanding how motor neurons reach the appropriate targets is necessary for the implementation of 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. And, as he also pointed out, 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. The Magellan mutation discovered by Pfaff's group was found in mice, but the affected gene, called Phr1, has also been identified in other model systems, including 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, much as ancient mariners who observed the stars and set their course accordingly. During development, the growth cone continuously pushes forward, while the lengthening neuron behind it matures into the part of the cell called the axon. Once the growing cell “lands” at its target in a muscle cell, it is the axon that will relay the messages that allow an animal to control and move its limbs at will.
In Magellan mutants, Pfaff's team discovered that the growth cone becomes disordered. Rather than 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.