Research Shows Role of Mechanical Signaling in Myelination

Their findings, published online June 6 in Nature Neuroscience, may signal a path to new therapies for multiple sclerosis and other myelin-related diseases.

Feltri and her colleagues found that Schwann cells respond to mechanical stimuli by activating certain molecules that are then transferred to the nucleus. This triggers the formation of myelin, the protective coating that neurons need to function.

“There were hints in previous studies that mechanical properties of tissues could influence the behavior of myelin-forming cells,” Feltri says.

“Our work proves for the first time, in vivo, that this is indeed the case. We have demonstrated that mechanical information is necessary for myelination to occur.”

The UB researchers reported that an important, evolutionarily conserved signaling pathway plays a role in myelination. The Hippo pathway determines organ size through cell proliferation and cell death, and is also implicated in some cancers.

The scientists found that two genes that this pathway controls, YAP and TAZ, are required in myelin production and are activated by mechanical forces.

When they deleted these genes in mouse models, the animals experienced severe peripheral neuropathy with symptoms such as tremor, weakness and atrophy.

“The effect is caused by an impairment in an important developmental step necessary for myelin to be generated in the peripheral nervous system,” Feltri says.

While most medical treatments for demyelinating disorders rely on altering chemical signals, scientists may be able to learn from, and capitalize on, the mechanical forces revealed in the UB research.

“In the future, we potentially will be able to exploit a tissue’s mechanical properties, including the density, tension or elasticity of some part of the brain or peripheral nerves,” Feltri says.

It has long been established that mechanical signaling plays a role in muscle and bone injury and repair, Feltri notes.

“We know, for example, that after a bone fracture, one should put weight on the broken bone because this mechanical stimulation improves the formation of new bone cells.

“Now we know that a similar phenomenon is occurring with myelin cells.”

Similarly, traumatic brain or nerve injury causes mechanical stimulation of neural cells, Feltri points out. Some hereditary neuropathies — such as hereditary neuropathy with liability to pressure palsies caused by the deletion of certain genes — result in demyelination only after a compression injury.

“Our work is beginning to shed light on the mechanisms that are at the basis of these diseases,” she says.

Feltri and her team will now focus on the physical properties of the nervous system and their effect on myelin diseases.

They work in the Hunter James Kelly Research Institute (HJKRI), one of only a handful of centers focused exclusively on myelin, myelin disorders and their treatment.

The HJKRI is part of UB’s New York State Center of Excellence in Bioinformatics and Life Sciences.

It was established in 1997 by Buffalo Bills Hall of Fame quarterback Jim Kelly and his wife, Jill, after their infant son, Hunter, was diagnosed with the inherited, fatal disorder Krabbe Leukodystrophy as an infant. He died in 2005 at the age of 8.

Scientists from the Jacobs School of Medicine and Biomedical Sciences and the UB School of Engineering and Applied Sciences collaborated on the published research, titled “YAP and TAZ Control Peripheral Myelination and the Expression of Laminin Receptors in Schwann Cells.”

It was funded with startup money to the HJKRI from New York State’s Empire State Development Corporation/Krabbe Disease Research Working Capital and the National Institutes of Health’s National Institute of Neurological Disorders and Stroke.

Yannick Poitelon, PhD, a senior postdoctoral fellow in Feltri’s lab, is the paper’s first author.

Other UB co-authors are:

• Ruogang Zhao, PhD, assistant professor of biomedical engineering
• Fraser J. Sim, PhD, assistant professor of pharmacology and toxicology
• Lawrence Wrabetz, MD, HJKRI director and professor of neurology and biochemistry
• graduate and undergraduate students in biochemistry, neurology, neuroscience and biomedical engineering

Other authors are from the University of Wisconsin-Madison and Mount Sinai Hospital in Toronto.