Key Nerve Navigation Pathway Identified

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Key Nerve Navigation Pathway Identified

http://www.sciencedaily.com/releases/2007/11/071121145008.htm

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 Pfaff, Ph.D, a professor in the Gene

Expression Laboratory, identifies a mutation they christened

Magellan, after the Portuguese mariner whose ship 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.

" The defect is found in the structure of the neuron itself, " said

Pfaff, noting that the fundamental pieces, such as the receptors

capable of reading cues, all seem to be present. Without the correct

orientation of receptors, however, signals cannot be read

accurately, resulting in growth going off course.

" A precise gradient normally exists across the cone, " said

Pfaff, " which is disrupted in the Magellan mutants. " As a result,

cells lose their polarity. They literally do not know the front end

from the back end, according to Pfaff. This sense of polarity is a

universal feature common to all growing neurons. Therefore, " 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, " he

said.

Pfaff and his group identified Magellan using a novel system they

had developed, in which individual motor neurons and axons can be

visualized fluorescently. They were able to screen more than a

quarter of a million mutations, and the mutations of interest were

rapidly mapped to known genes as a result of the availability of the

sequenced mouse genome -- a byproduct of the effort to sequence

entire genomes such as that in the human.

The Magellan mutation is located in a gene known as Phr1, which is

also active in other parts of the nervous system, indicating that it

most likely functions to steer other types of neurons, such as those

that enervate sensory organs or connect different regions of the

brain. Studies of Magellan may therefore shed light on how a variety

of neurological disorders might be treated with cell replacement

strategies.