role of proteins in neural development

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Research provides more evidence of communication between developing

nerves and blood vessels

18-Nov-2004 News-Medical.Net http://www.news-medical.net/?id=6366

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.

The research team, which included Medical Institute

investigators D. Ginty and M. ll, 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 s Hopkins University School of

Medicine, and Yutaka Yoshida in ll's laboratory at Columbia

University.

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 ll'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 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 ll's laboratory, was haphazard. Furthermore,

knockout mice lacking Sema3E, produced in the laboratory of co-author

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 ll. “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.”

ll 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.

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