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CELLS IN MOTION: Shedding new light on the mysteries of cell
motion during development
By David F. Salisbury
September 10, 2002
Proceeding from a single cell to a complex organism requires the intricate orchestration of a
number of biochemical processes. If any thing goes wrong the result is a defective fetus. One of
the most difficult of these processes to study is cell motion. Now biologists at Vanderbilt and the
University of Missouri have taken a major step towards understanding the mysterious molecular
processes that direct cells to the correct locations within a developing embryo: understanding that
the researchers hope will eventually provide treatments for babies with birth defects such as
spina bifida. They have done so by studying the zebrafish, a small fish from the Ganges River in
India that has become an important animal model for the study of development in vertebrates,
animals with backbones
In
the August issue of the scientific journal Nature Cell Biology, Lilianna Solnica-Krezel, an
associate professor of biological sciences at Vanderbilt, and Anand Chandrasekhar, assistant
professor of biological sciences at the University of Missouri, Columbia, report having found a key
protein that directs the massive cell migrations that take place during an early stage in the
development of the zebrafish.
They found that, not only does this protein, called Strabismus, direct the migration of cells that
gives the developing fetus its initial shape and structure but it is also required for the migration of
nerve cells within the developing zebrafish brain, a type of cell motion that also takes place during
human brain development.
The same protein has previously been identified in the development of the fruit fly, Drosophila
melanogaster, where it affects the orientation of cells that form the fly's wings and compound
eyes. A closely related protein found in mice is implicated in malformation of the neural tube, the
tubular structure that develops into the brain and spinal cord. Failure of neura l tube closure is the
underlying cause of spina bifida that afflicts between 800 to 1,000 babies born each year in the
United States.
RESEARCH DETAILS
Because the zebrafish genome is currently being sequenced, Solnica-Krezel and her colleagues
can employ the powerful tools of genomics in their studies. One of these methods is to examine
the effects of specific mutations.
In this case, Solnica-Krezel's research group explored what takes place during the early
development of a mutant called trilobite. (It was given this name because the developing egg
forms a pattern shaped like one of these prehistoric marine creatures.) During an early stage of
development called gastrulation, the cells begin converging from all sides of the spherical egg to
the embryonic axis where the body begins to form. What begins as a disordered, chaotic motion
changes into an orderly movement. As this happens the cells also change from a round to an
elongated, spindle shape.
"It's something like a mob transforming into an army," says Solnica-Krezel.
Her research group discovered that the trilobite mutations prevent the army from forming. Cell
motions continue to be disordered and do not develop the same sense of direction and purpose
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CELLS IN MOTION
in the mutant as they do in normal embryos. As a result, trilobite's development is stunted. The
scientists determined that the mutations disrupt the activity of a specific membrane protein, called
either Strabismus or Van Gogh.
Somewhat
later in zebrafish development, a number of motor neurons move from one part of the
brain to another. "We don't understand why they move because they can form the connections
they need from their original location," says Solnica-Krezel. But Chandrasekhar and his Missouri
team discovered that this movement does not take place in trilobite embryos.
In order to determine whether the neurons' failure to migrate was due to factors within the cell or
the extracellular environment, the researchers transplanted trilobite neurons in the brains of
normal embryos and normal neurons in trilobite brains. They found that none of the normal motor
neurons migrated when placed in a trilobite brain, whereas a third of the trilobite neurons
migrated when placed in normal brains. This led the scientists to conclude that the
Strabismus/Van Gogh protein must have both cellular and extracellular effects.
With further study, the researchers determined that the method of movement of both the gastrula
cells and the neurons was similar to that of an amoeba: they extend their bodies in the direction
they want to move and retract them from the opposite side. By analyzing movies of migrating
cells during gastrulation and of fluorescently labeled neurons, the biologists determined that the
trilobite cells moved much slower and their movements were more random than normal.
The results of their various tests suggest that the protein Strabismus/Van Gogh acts
independently of known signaling pathways in mediating neuron movement. If this proves to be
the case, then it provides “an entry point to elucidate the molecular basis of this class of neuronal
migration,” they conclude in the article.
Solnica-Krezel's research team included research associates Jason R. Jessen, Jacek
Topczewski and Diane S. Sepich along with graduate student Florence Marlow. Graduate student
Stephanie Bingham worked with Chandrasekhar. The research was funded by the National
Institutes of Health, the National Science Foundation and the Pew Scholars Program in the
Biomedical Sciences.
Original article (subscription required):
Jessen JR, Topczewski J, Bingham S, Sepich DS, Marlow F, Chandrasekhar A, Solnica-Krezel L. (2002) Zebrafish trilobite identifies new roles for
Strabismus in gastrulation and neuronal movements. Nat Cell Biol. Aug;4(8):610-5.
BIOGRAPHICAL SKETCH
Lilianna Solnica-Krezel was raised in a very small and very beautiful city in Poland. Sandomierz
is its name and it was more important in medieval times than it is today. As a young girl, she was
interested in many things, including poetry and literature. She thought that she might become a
journalist.
Her older brother, Bogdan, on the other hand, was interested in medicine. There were only two
government-controlled television channels and not a lot to do. So she began reading some of the
books he brought home and helped him out with his entries in science competitions.
Then she stumbled across a thick book about the physiology of organisms.
"I started to read it, and every chapter was a total revelation to me," she says. "One chapter
discussed development and I was totally fascinated. Another chapter was on lung function and I
was captivated. The same was true for the chapter on glycolysis. I’d been reading literature and
all that, but the science was just a fantastic thing for me. I got hooked on biology and from then
on my life was simple."
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CELLS IN MOTION
Having fixed on biology as a career, Solnica-Krezel left home to attend the University of
Warsaw. During her studies there, she came across two scientific papers about developmental
genetics with the fruit fly Drosophila. The authors reported finding that specific genes control the
development of specific parts of the fruit fly’s body.
"I was fascinated that you could use genetics like that," she says. As a result, her focus shifted to
developmental biology.
Later, as a graduate student at the University of Wisconsin in Madison, Solnica-Krezel was trying
to decide what aspect of developmental biology that she wanted to specialize in while she was
co-teaching a class in developmental genetics with her doctoral adviser, William F. Dove. So, she
decided to play a game with the students: Which animal was the best for studying development?
Worms? Fruitflies? Frogs? Zebrafish? Mice? When she concluded the exercise, "Zebrafish won,
at least in my mind!"
Shortly thereafter, she managed to get an invitation to visit Wolfgang Driever who was setting up
a zebrafish laboratory at the Harvard Medical School.
"When I saw zebrafish for the first time, I fell in love with them," she says. She went on to do a
post-doctoral fellowship with Driever where she had the opportunity to participate in the first major
genetic screening project for zebrafish. For more than four years, she and her colleagues
developed the procedures required to induce mutations in zebrafish and to use these mutants as
probes for studying developmental processes.
Following this intensive effort, she joined the faculty at Vanderbilt and set up her own zebrafish
laboratory.
Lilianna Solnica-Krezel's home page
MUTANT GALLERY
Suppose you are totally ignorant of how an internal combustion engine works and are given an
assignment to figure it out. One approach would be to take an engine completely apart and study
all the parts and how they fit together. When you did this you would be quite likely to work out
some aspects of its operation, such as the way the crankshaft turns linear motion into rotation.
But in some other areas, like carburetion and combustion, such an anatomical approach is far
less likely to be helpful. But there is another strategy that can: Removing parts (or replacing them
with parts of slightly different size or shape), reassembling the engine and noting the way that
engine runs or fails to run can provide you with an important additional source of information
about the engine’s design.
A living organism is millions of times more complex than a gas engine and one of the extremely
powerful ways that scientists have of studying it is use the power of genetics to replace naturally
occurring genes with slightly different genes (polymorphisms or mutations) and then studying how
the change affects the way in which the animal develops and functions. This is a technique that
Lilianna Solnica-Krezel and her fellow zebrafish researchers use extensively. Following are
images of a natural, or wild-type zebrafish embryo and embryos of mutants that have provided
valuable new insights into the development process. All the embryos shown are between 24 and
36 hours old.
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CELLS IN MOTION
LIFE OF A LAB FISH
Zebrafish have characteristics that make them ideal for developmental research. They lay eggs
that are transparent and develop outside the body, making them particularly easy to study.
Development is rapid, proceeding from fertilization to hatching in only three days. The fish are
easy and inexpensive to raise, so scientists can keep thousands of them in a laboratory. A major
project is underway to sequence the zebrafish genome, making the powerful tools of genomics
increasingly available.
ZEBRAFISH
LAB FACTS:
The lab houses about 15,000 fish in 3,500 tanks of varying sizes
Although zebrafish are relatively hardy, Nashville tapwater kills them within 5
minutes,
so the laboratory has two separate filtration systems to maintain water quality
 The lifespan of a zebrafish is between two to four years.
 Zebrafish breed about once a week. Typically, a female zebrafish will lay
hundreds of
eggs in a day. The record is 1,000 eggs by a single female in a day.
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