Scientists shed light on long-distance signaling in developing neurons

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Scientists shed light on long-distance signaling in developing neurons

http://www.eurekalert.org/pub_releases/2008-02/nyph-ssl021908.php

For the first time, functional transcription factor mRNA is found

outside the nucleus, at the tip of growing axons

A longstanding puzzle in neurodevelopment may have yielded up a key

secret.

A team led by scientists at Weill Cornell Medical College says they

have determined how events at the very tips of the developing

neuron's long, skinny axon affect gene transcription back in the

cell's distant nucleus.

The study also revealed the first-ever evidence of a transcription

factor -- proteins that influence gene activity -- working outside

the cell's nucleus.

The findings, published in the Feb. 1 issue of Nature Cell Biology,

could bring neuroscientists a much better understanding of how nerve

cells grow and connect during healthy development, and how these

processes might go astray in neurological disease.

" We have found a process whereby the growth cone at the developing

axon's tip sends key signals back to the cell nucleus to ensure the

neuron's survival, " explains senior study author Dr. Samie R.

Jaffrey, associate professor of pharmacology at Weill Cornell Medical

College. " In this way, the human nervous system develops over time,

choosing viable neural pathways over neurological 'dead ends.' This

process hinges on the type of communication between the growth cone

and the nucleus that we now describe. "

As Dr. Jaffrey explains, the developing fetus carries many times more

neurons than it will retain after birth. These newly formed neurons

send out long branches called axons that seek specific targets -- a

toe, for example, or a kidney or an eye. In recent years, scientists

discovered that as the axon reaches its target -- which may be many

centimeters away from the nucleus -- it senses a signal called nerve

growth factor (NGF), which is made by target tissues.

" Most axons never make it to their proper destination and the neurons

die off in a preprogrammed way, " Dr Jaffrey says. " But the axons that

correctly navigate to their destinations detect NGF which 'says' to

the neuron 'No, you've made it, you can survive.' In these rarer

cases, the neuron lives to become part of the nervous system. "

But how does this critical information get passed from the growth

cone at the tip of the axon back to the cell's " command center, " the

nucleus?

" That was the central mystery we sought to clear up in this work, "

Dr. Jaffrey says.

To do so, his team examined axonal growth cones for messenger RNA

(mRNA) -- bits of genetic material that help produce specific

proteins. The team used an innovative new technique developed by

study lead author Dr. Llewellyn J. , a postdoctoral researcher in

Dr. Jaffrey's lab. He coaxed axons to grow in such a way that the

scientists were able to sample mRNA in the growth cones alone.

" By doing so, we were able to build a library of mRNA found in those

growth cones, " Dr. said.

The experiment yielded one big surprise: a type of mRNA that produces

a transcription factor called CREB.

" Prior research elsewhere has shown that CREB is essential to

neuronal survival, " Dr. Jaffrey says. " But no one had ever thought it

might be active in the axon. "

The team next used cutting-edge fluorescent technology to track

CREB's activity in the presence of the " survival signal, " NGF.

" We watched CREB being produced in the growth cone and then saw it

travel back to the nucleus, " Dr. Jaffrey says. " This was astounding --

it suggested that the axonally-synthesized protein could have a role

in the nucleus, a very long distance away. "

It is this axonally produced CREB that appears to be key to switching

off the neuron's self-destruct mechanism, he says. " The axonal CREB

enters the nucleus, where it induces gene expression that ensures

that the developing neuron will survive, " Dr. Jaffrey says.

This was confirmed in a later experiment where the team selectively

abolished CREB mRNA from the axons but not the rest of the

neuron. " When that happened, the neurons died, even in the presence

of NGF, " Dr. Jaffrey says. " This proves that axonal CREB, not CREB in

the nucleus, is the key player here. "

The findings may have big implications for neuroscience going

forward. First of all, they shed important new light on how the

complex system of interconnected neurons develops over time, and how

aberrations in this axon-to-nucleus relationship might impair that

development.

" We are also wondering if the type of phenomenon we have observed

might occur at other points in development, such as when axons

navigate through tissues to find their targets or when axons arrive

at targets and create synapses -- the electrochemical bridges between

neurons, and target cells, " Dr. Jaffrey says. " This newly discovered

property of the axon -- its ability to produce its own functional

transcription factors -- might allow axons to communicate with the

nucleus throughout neurodevelopment. "

And because runaway neuronal death is a hallmark of Alzheimer's

disease, spinal cord injury and other neurological injuries or

illness, insights into mechanisms controlling neuronal survival are

bound to be useful for medical research, the scientists say.

" We believe other mRNAs, and other transcription factors, may play

key roles as well, " Dr. Jaffrey says. " This exciting work marks a big

step forward in our understanding of neurodevelopment, as well as

neurological health and disease. "