2-way cell talk provides clues about neuromuscular disease

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2-way cell talk provides clues about neuromuscular disease

http://www.eurekalert.org/pub_releases/2008-02/mcog-tct021408.php

It's a scientific given that neurons tell other cells what to do, but

new evidence suggests that, like with any good relationship, these

target cells also have much to contribute, scientists say.

In an animal model, Medical College of Georgia researchers have shown

that if a muscle cell fails to produce the protein beta-catenin, its

neuron doesn't develop or function properly.

Their finding provides some of the first proof that in vertebrates

such as man, this retrograde communication – from the target cell

back to the neuron – is essential, says Dr. Lin Mei, corresponding

author on research published online Feb. 17 in Nature Neuroscience.

" Previously, we thought signals flow mainly from neuron to muscle.

This shows they can be produced from muscle, " says Dr. Mei, MCG's

chief of developmental neurobiology and Georgia Research Alliance

Eminent Scholar in Neuroscience. " This is some of the first clear

genetic evidence that when you disturb something in the muscle, you

have a nerve problem. "

Dr. Mei's research team knocked out beta-catenin in the muscle cells

of a developing mouse. As a result, nerve terminals, which reach out

to target cells, were misaligned. Release of neurotransmitters, which

enable cell talk, from the tiny vesicles inside nerve terminals was

impaired. Mice died prematurely. " Two-way communication is absolutely

essential, " he says. Interestingly when the researchers knocked beta-

catenin out of neurons instead, neurons developed and functioned

normally.

" Theoretically the finding is very important in that it supports the

retrograde hypothesis, " Dr. Mei says. " Practically it is also

important because problems with motor neuron survival and

differentiation cause many neuromuscular diseases, such as muscular

dystrophy and ALS, where motor neurons need to survive, " noting that

it's unknown why neurons die in these diseases.

" We believe there is a retrograde signal downstream of beta-catenin

or regulated by beta- catenin, " says Dr. Mei. " If you don't have beta-

catenin in the muscle, that signal may be missing and motor neurons

are not happy. "

To find out what that signal is, his lab is comparing genetic

expression in the beta-catenin knockout mouse to that of a normal

mouse to see which genes are up- or down-regulated. " Those genes may

be targeted by beta-catenin and may serve as this retrograde signal.

If we can identify that, I can retire, " says Dr. Mei.

Beta-catenin is a protein with many roles, including helping cells

stick together, and regulating gene expression in the Wnt pathway,

which is essential for development. Dr. Mei's previous work has shown

that at least in a Petri dish, when a signaling component of the Wnt

pathway, called disheveled, is disturbed in muscle cells, it causes

problems with their co-cultured neurons.

In the early 1900s, German-born Scientist Viktor Hamburger provided

some of the first evidence of the importance of retrograde

communication in proper development of motor neurons: when he removed

the budding limbs of chick embryos, motor neurons decreased in

number.

" … (T)he use of transgenic animals has established the importance of

muscle ß-catenin in (neuromuscular junction) formation in vivo, "

write Drs. Amy K.Y. Fu, Zelda Cheung and Y. Ip, of Hong Kong

University of Science and Technology in an accompanying News and

Views. " These findings also underscore the emerging role of Wnt

signaling proteins in the regulation of synapse development. The

identification of muscle ß-catenin-dependent signals for motoneurons

may also contribute to our understanding of neuromuscular disorders,

including muscular dystrophy and amyotrophic lateral sclerosis. "

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Dr. Xiao-Ming Li, MCG assistant research scientist, and Dr. Xian-ping

Dong, former postdoctoral fellow in Dr. Mei's lab, are co-first

authors. Other MCG authors include Shi-Wen Luo, Dr. Bin Zhang, Dae-

Hoon Lee, Annie K.L.Ting, Hannah Neiswender, Chang-Hoon Kim, Ezekiel

Carpenter-Hyland, Tian Ming Gao and Dr. Wen-Cheng Xiong.

Dr. Mei's research is funded by the National Institutes of Health and

the Muscular Dystrophy Association.