New Roles For Growth Factors: Enticing Nerve Cells To Muscles

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New Roles For Growth Factors: Enticing Nerve Cells To Muscles

http://www.medicalnewstoday.com/medicalnews.php?newsid=45344

During embryonic development, nerve cells hesitantly extend tentacle-

like protrusions called axons that sniff their way through a

labyrinth of attractive and repulsive chemical cues that guide them

to their target.

While several recent studies discovered molecules that repel motor

neuron axons from incorrect targets in the limb, scientists at the

Salk Institute for Biological Studies have identified a molecule,

known as FGF, that actively lures growing axons closer to the right

destination. Their findings appear in the June issue of Neuron.

" The most important aspect of our finding is not necessarily that we

finally nailed the growth factor FGF as the molecule that guides a

specific subgroup of motor neurons to connect to the muscles that

line our spine and neck, " says senior author Pfaff, Ph.D., a

professor in the Gene Expression Laboratory, " but that piece by

piece, we are uncovering general principles that ensure that the

developing nervous system establishes proper neuronal connections. "

Understanding how axons find their destinations may help restore

movement in people following spinal cord injury, or those with motor

neuron diseases such as Lou Gehrig's disease, spinal muscle atrophy,

and post-polio syndrome. Failure to establish proper connectivity in

the brain may also underlie autism spectrum disorders and mental

retardation.

The multitasking members of the FGF growth factor family regulate

blood vessel formation, wound repair, lung maturation, and

development of skeletal muscle, blood and bone marrow cells. The Salk

study adds on more job to an already long list.

" Our study emphasizes that the nervous system does not necessarily

rely on an entirely new set of molecules to govern axon navigation,

but instead uses growth factors already involved in embryonic

development in clever and novel ways, " Pfaff says.

Skeletal muscle consists of thousands of muscle fibers, each

controlled by one motor neuron whose cell body lies in the brain or

spinal cord. Connections between muscle and nerve cells are

established embryonically when newborn neurons extend axons to " wire "

the appropriate muscle fiber.

The wiring process is highly orchestrated - each motor neuron has

already pledged allegiance to a particular muscle fiber before it

reaches out to connect with its predetermined partner. But until now,

scientists could only speculate how the invisible bond was formed.

" The question was how do these motor neurons know where to go, " says

Pfaff. " It would be a disaster if you wanted to move your arm and

instead bent your back. "

Earlier studies suggested that muscles lining the spine sent out

chemical cues as a siren song for specific motor neurons known as

MMCm cells. But when attempts to identify the enticing substance

failed, many started to doubt its existence.

After screening numerous candidates, the Pfaff team found not only

that FGF is expressed in target muscle, but that FGF " sensors, " known

as FGF receptors, are expressed in MMCm motor neurons. Furthermore,

MMCm axons could not " hear " their muscle partner's call and failed to

reach their destination in mouse mutants lacking the sensor molecule.

Finally, using mice engineered to express a fluorescent protein in

MMCm neurons, the investigators demonstrated that only the glowing

neurons extended axons in the direction of target cells expressing

FGF.

" After a lot of hard work, we narrowed it down to FGFs and showed

that they were indeed the long sought-after mysterious substance, "

says Pfaff. Neural stem cells can now be coaxed to develop into motor

neurons in a test tube. In that artificial environment, explains

Pfaff, " Most external cues that guide immature motor neurons during

embryonic development will be missing. " Hence the need to identify

axon guidance factors. He continues, " It is not enough to make the

right cell type, you need to connect them to the right target. Growth

factors like FGF may be crucial to persuade and guide them towards

the desired destination. "

Additional contributors to this study included first author Ryuichi

Shirasaki, Ph.D., a former postdoctoral fellow in Pfaff's lab and now

a faculty member at Osaka University, Japan; postdoctoral fellow

ph W. Lewcock, Ph.D.; and research assistant Lettieri, both

at Salk.