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Current issue
Neurons on the move
How a structure called the centrosome leads a nerve cell's two-step migration in the brain
BY BETSY HANSON
“One of the most wonderful moments as a
scientist comes when you feel your mindset shift,” says
Rockefeller’s Mary Beth Hatten. “In our case, we
realized that the paradigm we used to design experiments was not
going to yield the answer about what controls how brain cells
migrate during development.”
Hatten studies how early nerve cells in the
brains of developing mammalian embryos move outward from the
central area of the brain where they are generated.
“Scientists have spent the last 15 years focusing on specific
adhesion systems as the most important aspect of cell
migration,” she says, referring to the way nerve cells stick
to, and later detach from cells called glia that guide them to
their destinations in the developing brain.
As one aspect of the studies on surface
receptors, Hatten and colleagues examined the cytoskeleton —
the scaffold of elements called microtubules that support a
cell’s three-dimensional shape — of migrating neurons.
That work showed a unique bingo-cage like structure around the
nucleus that appeared to hold the nucleus as the cell moved. The importance of the
cytoskeleton to brain development gained even more prominence as
several genes that cause severe developmental defects in humans
turned out to code for proteins that attach to the cytoskeleton.
Now Hatten, who is the university’s
Frederick P. Rose Professor and head of the Laboratory of
Developmental Neurobiology, shows that it is not the relationship
of the cytoskeleton to adhesion molecules, but a novel signaling
protein within the cytoskeletal system that is critical to the pace
of the cell’s migration.
The new study, published in the November issue
of Nature Neuroscience, shows that a surprising mechanism underlies the
migration of nerve cells in the developing embryo. The Rockefeller
researchers report that the cells move in a two-part
“step” led by a structure within the cell called the
centrosome. Once the centrosome, the key organizing point for the
cell’s internal skeleton, moves forward, the nucleus follows.
The Rockefeller scientists produced time-lapse
movies that show nerve cell migration in unprecedented clarity and
detail.
“It’s almost like a little
inchworm in the way it moves,” says Hatten, whose time-lapse
movies first revealed this motion in 1987. With each step the cells
travel a little more than a micron, or about half the width of a
hair over the course of an hour. Translated to a human scale, they
would travel as far as the distance between New York and Chicago in
order to find their place in the right layer of the developing
network of the brain.
New microscopic techniques allowed the
researchers to probe the internal dynamics of migrating nerve cells
in real time in living cells. The scientists knew that disrupting
the cytoskeleton with chemicals prevents the cell from moving and
that problems with the cytoskeleton are implicated in human
disorders in which nerve cells fail to migrate normally. But no one
had previously watched the cytoskeleton in living neurons in real
time. Also they knew that the nucleus is surrounded by a
special cytoskeletal “cage,” but they did not know the
function of these elements.
The researchers took a new type of fluorescent
dye called Venus, which glows 20 times brighter than other dyes,
and tagged the microtubules of a type of mouse neuron called a
granule cell. Rockefeller’s Tarun Kapoor, an expert on the
centrosome and on techniques for visualizing microtubules,
collaborated with Hatten and her lab colleagues to create images
showing these structures in extraordinary detail. Kapoor is head of
Rockefeller’s Laboratory of Chemistry and Cell Biology.
When the scientists looked at the cells with a
spinning disk confocal microscope in the university’s
Bio-Imaging Resource Center, the dye revealed a cage-like structure
around the cell’s nucleus, proving the existence of this
structure, whose role in cell migration has been debated by many
scientists. The Rockefeller researchers settled the debate by
showing that while the cage around the nucleus is essential for the
cell to migrate because it holds the nucleus in place, it does not
actually control cell movement.
Next the researchers looked at the protein
Par6-alpha, referred to as mPar6-alpha in mouse cells. Par6 is one
a group of proteins that signal cell polarity in the worm C. elegans. Recent
studies in other laboratories located a mammalian counterpart of
the worm gene, and led the scientists to theorize that mPar6-alpha
might orient the young neuron on the glial wire during migration.
Also, screens for genes that were enriched in migrating cells by a
method called gene chips had indicated a high level of Par6 in
migrating granule neurons. As a result, Hatten and her coworkers
suspected that mPar6-alpha was active during migration.
Again, the researchers used Venus, this time to label
mPar6-alpha protein. Its bright green glow concentrated in the
centrosome, the organelle located just in front of the nucleus in
migrating cells. “The centrosome has a large number of
proteins that make up its structure. Most other known proteins in
the centrosome are structural,” says Hatten. “mPar6 is
the one of the first signaling proteins found there.”
But the brightly labeled centrosome led the
scientists to an even more important discovery. Watching the cells
with labeled mPar6-alpha as they moved along the glial fibers, the
researchers could see a two-step process to every advance the cells
made. First the centrosome slid forward, and then three minutes
later the nucleus followed.
“The timing of the advance of the
centrosome and then of the nucleus was exactly the same as the
timing we measured 15 years ago that it takes for the nerve cell to
adhere, let go and take a new step along the glial monorail,”
says Hatten. Additional experiments that tagged a different
component of the centrosome confirmed these results.
To further investigate the function of
mPar6-alpha, the researchers created cells with either too much or
too little of the protein. In both cases the cells sat motionless
on their glial fibers.
“In response to mPar6-alpha, the
centrosome is playing a signaling role in setting the cadence for
migration of the cell,” says Hatten.
November 19, 2004 |
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