http://unisci.com/stories/20021/0117024.htm
17-Jan-2002
Biologists have observed, for the
first time, a protein gradient in developing fruit fly embryos believed
to trigger the division of the embryo into nervous system and different
types of epidermis within complex organisms such as humans.
The work was performed at the University
of California, San Diego.
In a paper featured on the cover
of this month's issue of the journal Developmental Cell, the scientists
demonstrate visually and in experimental detail the molecular process by
which an embryo begins partitioning itself for subsequent development into
neural and distinct forms of epidermal tissue.
Their experiments provide final confirmation
of an elegant hypothesis proposed during the 1950s by mathematician Alan
Turing, who suggested that chemicals generated incrementally during the
development of a complex organism might cause the differentiation of cells
during early embryonic development.
"We are now one step closer to understanding
the mechanism by which crude spatial information provided by the egg is
converted into more refined information that ultimately defines every position
along the body axis in exquisite detail," says Ethan Bier, a professor
of biology at UCSD who headed the research. "This process assures that
fingernails grow only on the tips of fingers and two eyes become positioned
symmetrically on either side of the nose."
Turing suggested that the chemicals
responsible for the developmental changes in the embryo, which he dubbed
"morphogens," were produced and secreted by one group of cells, then diffused
into neighboring cells where they were destroyed at a certain rate.
According to Turing, the juxtaposition
of cells producing the morphogen with adjacent cells acting as a sink to
remove that substance would create a balanced situation leading varying
concentrations of that substance depending on its distance from the source.
Cells close to the source would be
exposed to high levels of the morphogen while those further away would
see lower levels. Those differences, Turing thought, would provide the
instructions to differentiate cells during development.
Turing's idea spurred a search for
these morphogens and, over the past two decades, several proteins were
identified that appear to possess many of the characteristics he proposed
for morphogens.
One of these proteins, which is known
to promote the early development of the nervous system in animals as diverse
as humans and insects, is called Chordin in humans and Short Gastrulation,
or Sog for short, in fruit flies.
Chordin and Sog, sometimes referred
to as neural inducers, work by binding to and inactivating the effect of
other secreted factors known as BMPs. The neural inducers prevent BMPs
from actively suppressing the default preference of the embryonic cells,
which is to become neural tissue.
"Neural inducers have remarkably
similar functions in insects and humans as highlighted by the fact that
one can inject Sog into the region of a frog embryo that normally would
give rise to epidermis and induce the formation of a second frog nervous
system at that position," says Bier.
Neural inducers also have an effect
on the kind of epidermal tissue that forms next to the nervous system.
Consistent with Turing's model, some
scientists believed that Sog diffused into neighboring epidermal cells
to suppress BMP activity, creating two zones of differential BMP activity
-- one of which becomes epidermis proper and the other of which forms a
tissue similar to amniotic tissue. However, no one was able to demonstrate
that Sog was present in a graded fashion as predicted by this model.
The reason, it turned out, was that
the levels of diffusing Sog protein were much too low to be detected by
available histochemical methods.
Shaila Srinivasan, a postdoctoral
researcher in Bier's laboratory, overcame that impediment by developing
a sensitive fluorescence detection technique that made it possible to directly
observe the accumulation of Sog outside of the area in which it is synthesized.
"Having established that we could
visualize the graded distribution of Sog in normal embryos, we then tested
the hypothesis that an enzyme produced in the epidermal region called Tolloid,
which cleaves and inactivates Sog, might be responsible for this," says
Bier, whose work was financed by the National Institutes of Health.
"We did this by examining the pattern
of Sog accumulation in mutants lacking function of the Tolloid gene," Bier
said. "We observed that in the absence of Tolloid, Sog levels are greatly
elevated in epidermal cells and accumulate steadily until the entire embryo
contains nearly uniform amounts of Sog.
"We also found another cellular function
that limits epidermal Sog levels -- a process known as endocytosis, through
which proteins are taken up from the outside of the cell.
"These studies provide the final
link demonstrating that Sog is a morphogen and explain how the graded distribution
of Sog is created."
Related image:
Graphic showing division of dorsal
region of developing embryo [yellow] caused by protein gradient [color
photo]. Graphic Credit: Ethan Bier, UCSD; Photo Credit: Shaila Srinivasan,
UCSD
Copyright © 1995-2002 UniSci
Contact: Ethan Bier, Kim McDonald
http://ucsdnews.ucsd.edu/graphics/images/DV_emb._epiSog.jpg
