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New roles for growth factors: Enticing nerve cells to muscles
June 16, 2006La Jolla, CA—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 15 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 Samuel 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 Joseph W. Lewcock, Ph.D.; and research assistant Karen Lettieri, both at Salk.
Salk Institute
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 Joseph W. Lewcock, Ph.D.; and research assistant Karen Lettieri, both at Salk.
Salk Institute
Motor Neurons News and Current Motor Neurons Events RSSProtein plays Jekyll and Hyde role in Lou Gehrig's disease
Amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig's disease, is a fatal neurodegenerative disease caused by the death of motor neurons in the brain and spinal cord that control muscle movements from walking and swallowing to breathing. In a groundbreaking study this week in PLoS Biology, Brandeis and Harvard Medical School scientists report key findings about the cause and occurrence of the familial form of ALS.
Umbilical cord blood cell transplants may help ALS patients
A study at the University of South Florida has shown that transplants of mononuclear human umbilical cord blood (MNChUCB) cells may help patients suffering from Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease.
Lou Gehrig's protein found throughout brain, suggesting effects beyond motor neurons
Two years ago researchers at the University of Pennsylvania School of Medicine discovered that misfolded proteins called TDP-43 accumulated in the motor areas of the brains of patients with amyotropic lateral sclerosis (ALS), or Lou Gehrig's disease.
Penn researchers gain new insights on spinal muscular atrophy
Researchers from the University of Pennsylvania School of Medicine discovered that the effect of a protein deficiency, which is the basis of the neuromuscular disease spinal muscular atrophy (SMA), is not restricted to motor nerve cells, suggesting that SMA is a more general disorder.
Leaky blood vessels open up nerve cells to toxic assault in Lou Gehrig's disease
Leaky blood vessels that lose their ability to protect the spinal cord from toxins may play a role in the development of amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig's disease, according to research published in the April issue of Nature Neuroscience.
Cold Spring Harbor Laboratory Scientists Devise Potential Approach To Treat Spinal Muscular Atrophy
In the neuromuscular disease called spinal muscular atrophy, or SMA, a protein deficiency caused by a single gene mutation leads to serious damage in growing nerve cells and the muscles they control.
Researchers identify a gene responsible for cases of Lou Gehrig's disease
A team of Canadian and French researchers has identified a novel gene responsible for a significant fraction of ALS (sporadic amyotrophic lateral sclerosis) cases. ALS is commonly referred to as Lou Gehrig's disease, an incurable neuromuscular disorder that affects motor neurons and leads to paralysis and death within one to five years.
Gene newly linked to inherited ALS may also play role in common dementia
Scientists at Washington University School of Medicine in St. Louis have linked a mutation in a gene known as TDP-43 to an inherited form of amyotrophic lateral sclerosis (ALS), the neurodegenerative condition often called Lou Gehrig's disease.
Targeting astrocytes slows disease progression in ALS
In what the researchers say could be promising news in the quest to find a therapy to slow the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, scientists at the University of California, San Diego (UCSD) School of Medicine have shown that targeting neuronal support cells called astrocytes sharply slows disease progression in mice.
Mutation may cause inherited neuropathy
Mutations in a protein called dynein, required for the proper functioning of sensory nerve cells, can cause defects in mice that may provide crucial clues leading to better treatments for a human nerve disorder known as peripheral neuropathy, which affects about three percent of all those over age 60.
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