A mutation named Magellan steers nerve cells off course
November 21, 2007
LA JOLLA, CA — 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.
"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.
Lead author on the study is Joseph W. Lewcock, formerly a
postdoctoral fellow in Pfaff's laboratory and currently at Genentech,
Inc. Additional Salk authors include postdoctoral fellow Nicolas
Genoud and senior research assistant Karen Lettieri.
The study, titled "The ubiquitin ligase Phr1 regulates axon outgrowth
through modulation of microtubule dynamics," was supported by the
National Institute for Neurological Disorders and Stroke.
The Salk Institute for Biological Studies in La Jolla, California, is
an independent nonprofit organization dedicated to fundamental
discoveries in the life sciences, the improvement of human health and
the training of future generations of researchers. Jonas Salk, M.D.,
whose polio vaccine all but eradicated the crippling disease
poliomyelitis in 1955, opened the Institute in 1965 with a gift of
land from the City of San Diego and the financial support of the
March of Dimes.
http://www.salk.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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