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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.

  • Watch a movie of migrating neurons


  • November 19, 2004



     

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