Killer competition: Neurons duke it out for survival

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Killer competition: Neurons duke it out for survival

http://www.eurekalert.org/pub_releases/2008-05/jhmi-kcn050608.php

The developing nervous system makes far more nerve cells than are

needed to ensure target organs and tissues are properly connected to

the nervous system. As nerves connect to target organs, they somehow

compete with each other resulting in some living and some dying. Now,

using a combination of computer modeling and molecular biology,

neuroscientists at s Hopkins have discovered how the target

tissue helps newly connected peripheral nerve cells strengthen their

connections and kill neighboring nerves. The study was published in

the April 18th issue of Science.

" It was hard to imagine how this competition happens because the

signal that leads cells to their targets also is responsible for

keeping them alive, which begs the question: How do half of them

die? " says Ginty, Ph.D., a professor of neuroscience and

investigator of the Medical Institute.

Target tissues innervated by so-called peripheral neurons coax nerves

to grow toward them by releasing nerve growth factor protein, or NGF.

Once the nerve reaches its target, NGF changes from a growth cue to a

survival factor. In fact, when some populations of nerve cells are

deprived of NGF they die. To further investigate how this NGF-

dependent survival effect works the researchers looked for genes that

are turned on by NGF in developing nerve cells.

They found hundreds of genes that respond to NGF genes, some of which

are involved in enhancing NGF's effect. With the observation that NGF

seems to control genes that improve NGF effectiveness, Ginty's team

hypothesized that this could be the way in which nerve cells compete

with one another for survival. To test this idea the team turned to

colleagues at the Mind/Brain Institute at Hopkins who specialize in

computer modeling of such problems.

The computer model they built assigns each nerve cell its own

mathematical equation that take into account how much NGF the cell

encounters or how effective NGF can be to simulate a cell's drive to

survive. When they plugged in the model, it showed that over time-

about 100 days or so-about half of the cells manage to survive, while

the other half die.

But, in the developing mouse embryo, nerve cells that die do so over

the course of two to three days just before birth. " So then we

considered whether these nerves compete like other systems in the

body, where those with stronger connections punish the weaker ones, "

says Ginty. The team turned their attention to other genes they found

to be NGF dependent; two of which code for proteins that kill

neighboring nerve cells and another is the receptor for these death

proteins.

According to Ginty, nerves that connect to muscles undergo a similar

process called synapse elimination where stronger connections stay

connected and weaker ones are eliminated. The team wondered if this

is also true of peripheral nerve cells competing for NGF availability

and ultimate cell survival. To test this idea they plugged these

three additional genes into their computer model, assuming that the

stronger connected nerve cell punishes its neighbors by releasing the

two proteins capable of killing. The computer model showed again,

that half the nerve cells die over time, but this time the death

occurred over two to three days rather than 100 days, just as in

living animals.

To confirm that the model is accurate, the team went back to

genetically altered mice. They predicted that removal of the

punishment signals should delay cell death as observed in their early

computer simulations. Indeed, nerve cells in mice lacking the

receptor protein for the death signals died much slower than in mice

with the receptor protein intact.

" I never would have believed that these three genes could speed up

competition so much, " says Ginty. " But there it was in front of us-it

was amazing. "