November 18, 2004
A "Repulsive" Protein Guides Blood Vessel Development
In a developing embryo, the growth of nerves cannot outpace the
establishment of life-giving blood vessels. Now, researchers have found
that a protein intimately involved in blood vessel patterning actually
belongs to a family of proteins known to guide neural development.
The researchers said the studies provide more evidence of
communication between developing nerves and blood vessels.
Understanding how those networks talk to each other could help
researchers devise methods to prevent blood vessel growth in tumors
selectively - an approach to cancer treatment known as
anti-angiogenesis.
 | | | | |  |  | | | | |  |  | Blood Vessel Development
The image shows a low magnification picture of the mouse vasculature. The vessels along the trunk region are patterned by the Sema3E-plexin-D1 signaling module. more
Photo: Laboratory of David Ginty/HHMI at The Johns Hopkins University School of Medicine
|
|
| | |
| | | |
The research team, which included Howard Hughes Medical Institute
investigators David D. Ginty and Thomas M. Jessell, published its
findings November 18, 2004, in Science Express, the early
online version of the journal Science. Co-first authors of the
paper were Chenghua Gu in Ginty's laboratory at The Johns Hopkins
University School of Medicine, and Yutaka Yoshida in Jessell's
laboratory at Columbia University.
“One possibility is that drugs that mimic this function could be useful in preventing growth of the new blood vessels required by tumors.”
David D. Ginty
In their experiments, the researchers explored the roles of two
proteins involved in vascular development. One of the molecules,
Semaphorin 3E (Sema3E), is a member of a family of protein signals that
guides the growth of nerve cells. The other protein, plexin-D1, is a
receptor protein that nestles in the membranes of growing cells and
responds to external signaling proteins.
Ginty said that before the current study, plexin-D1 was known to be
important for vascular development, but the specific signal to which it
responded was a mystery. The molecule was also considered an important
receptor in nerve cell development, and for that reason Jessell's
laboratory was actively investigating plexin-D1.
Studies by Ginty and others, including former HHMI investigator Marc
Tessier-Lavigne, who is now at Genentech, had shown that some of the
semaphorins bind to a receptor called neuropilin, which is critical for
vascular patterning in the embryo. However, in their earlier work, Gu,
Ginty, and co-author Alex Kolodkin showed that semaphorins do not need
to bind to neuropilin for normal patterning to occur.
“That work set us looking for other potential mechanisms by
which semaphorins might control vascular pattern development,”
said Ginty. The researchers found Sema3E in regions of the developing
embryo that suggested that it should have a role in the patterning of
blood vessels. They also found a strikingly similar pattern of
expression of the blood vessel cell receptor plexin-D1, leading the
researchers to hypothesize that Sema3E might be the signaling molecule
that interacts with plexin-D1. If this were true, it suggested that
Sema3E exerts a “repulsive” force, channeling the blood
vessels to grow along their proper course.
Meanwhile, Yoshida discovered that unlike other members of the same
protein family, Sema3E binds selectively to plexin-D1 - a strong hint
that the two signals work together to control vascular patterning.
Yoshida also found that Sema3E can bind to plexin-D1 whether or not it
binds to neuropilin.
Researchers noted that in contrast to the careful patterning of
blood vessels in normal mice, the pattern of blood vessels in mice
lacking plexin-D1, produced in Jessell's laboratory, was haphazard.
Furthermore, knockout mice lacking Sema3E, produced in the laboratory
of co-author Christopher Henderson of the Developmental Biology
Institute in France, showed the same defective patterning.
In additional experiments, Gu showed that overexpression of Sema3E
protein in specific regions of chick embryos prevented vascular growth
into those areas.
“Sema3E is a very potent chemorepellent for developing blood
vessels,” Ginty noted. “So, one possibility is that drugs
that mimic this function could be useful in preventing growth of the
new blood vessels required by tumors.”
“One of the really interesting things about this paper is that
it questions the idea that Sema3E's binding to neuropilin is required
for vascular patterning,” said Jessell. “This, together
with the finding that Sema3E interacts with plexin-D1, independent of
neuropilin, may turn some of the preconceptions about the role of
neuropilins in vascular patterning on their head.”
Jessell and his colleagues are now exploring whether Sema3E and
plexin-D1 also contribute to the development of connections in the
spinal cord. Ginty and his colleagues plan to explore the role of the
proteins in neural development, as well as whether the combination is
involved in vascular patterning in the limbs.
|
