How to insulate a stripped nerve

Without a sheath called myelin, electrical impulses would travel through our nervous system along the biological equivalent of naked wires. Energy would be lost and signals would never reach distant locations in the body. Evolution produced a solution that would be familiar to any electrical engineer: insulators. In the body this function is performed by cells that manufacture high amounts of myelin, which is a mixture of protein and fat molecules called lipids. Then they wrap themselves in sheaths around the long, wire-like axons of neurons. In a number of serious diseases, the sheaths break down in an irreversible process that disrupts communication, leading to the death of nerve cells and ultimately the affected human or animal. Now in a collaborative project with other MDC groups, Carmen Birchmeier’s lab has found a signaling system in cells which can activate the production of myelin proteins. The work was published in a recent edition of Genes and Development.

Myelinating cells (blue and green) wrap themselves around axons (yellow) to form sheaths that serve as insulators. Activating Mek1 increases the production of myelin and leads to sheaths that are thicker than normal (green). The difference is easiest to see in older mice (P30), in whom myelination usually slows down as a result of normal aging. Animals with active Mek1 continue to produce thick sheaths.

In the peripheral nervous system (outside the brain and spinal cord), specialized Schwann cells produce huge quantities of myelin, undergo massive expansions of their membranes, and wrap themselves around axons. In mice this process starts around birth and continues into adulthood, but at some point it falls off. Initially external signals such as growth factors, provided by the axon, activate genes that produce myelin and lipid-producing enzymes in Schwann cells. This triggers the transcription of the genes into RNA molecules and must be followed by a second step – the translation of RNA into proteins – for the cells to assume their proper functions in the nervous system.

“The amount of myelin that cells produce needs to be precisely controlled,” Carmen says. “Axons have various diameters, and their size determines the thickness of the sheath. Quite a bit is known about the biochemical signals that promote or block myelin transcription, but technical limitations have prevented us from getting a close look at the second step, translation. This is what we have addressed in the current project.”

Matthias Selbach’s lab at the MDC has developed a method of observing the times and rates at which proteins are synthesized from RNAs in mice. The method is based on pulsed SILAC (for stable isotope labeling with amino acids in cell culture) which involves transferring cells from one growth medium to another. The first contains normal forms of amino acids, the building blocks used to make proteins. In the second medium, some amino acids include nonradioactive heavy isotopes. These markers can be detected in an instrument called a mass spectrometer. Scientists can then study protein populations in cells and precisely distinguish between molecules synthesized before the transfer and those created afterwards.

Erik McShane has now further developed this pulsed SILAC technique to allow the method to be used in mice and other living organisms. Animals are given milk or food containing amino acids labeled with the heavy isotopes. The change has no adverse effects on their health and allows scientists to observe the time points and the rates at which specific proteins are produced.

Previous work from Carmen’s lab and others had revealed that a molecule called Neuregulin-1, or Nrg-1, normally triggers the transcription of myelin RNA through a cellular biochemical pathway called MAPK. Such pathways change the behavior of many molecules; stimulation with Nrg-1 activates other molecules called ErbB3 and Shp2. Interfering with these molecules or other targets of the signal disrupted the development of Schwann cells and the production of myelin sheaths. The MAPK pathway is normally tuned down over the course of aging, meaning that at some point in adulthood, Schwann cells lose most of their ability to replenish or repair the myelin.

In the current study, Maria Sheean, Cyril Cheret and other members of Carmen’s lab discovered an alternative pathway by which cells can trigger myelin production. “We stimulated MAPK signaling with another signal, a form of the molecule MAP kinase kinase 1, or Mek1,” Carmen says. “This activates proteins called Erk1, Erk2, S6 and eIF4E and results in a continuous production of new myelin proteins and enzymes that produce lipids. Using the SILAC method, we saw that this isn’t happening because cells are producing new RNAs. Instead, it is because many RNAs that have been put ‘on hold’ are now being translated into proteins.”

The scientists discovered that mice which had been genetically modified to produce an overactive form of Mek1, called Mek1DD, produced higher-than-normal amounts of myelin. This had two effects: it prevented the drop in myelin production that normally accompanies aging. Additionally, it led to the formation of thicker myelin sheaths around some axons, in some cases so thick that they compressed the nerve.

The findings offer a potential new target in the search for new ways to treat diseases that affect myelin sheaths. “Mek1DD activates MAPK signaling and overcomes the control mechanisms that normally end myelination,” Carmen says. “This suggests that activating MAPK might restimulate the production of the protein and allow Schwann cells to reinsulate damaged nerves.”

- Russ Hodge

Highlight Reference:

Sheean ME, McShane E, Cheret C, Walcher J, Müller T, Wulf-Goldenberg A, Hoelper S, Garratt AN, Krüger M, Rajewsky K, Meijer D, Birchmeier W, Lewin GR, Selbach M, Birchmeier C. Activation of MAPK overrides the termination of myelin growth and replaces Nrg1/ErbB3 signals during Schwann cell development and myelination. Genes Dev. 2014 Feb 1;28(3):290-303.

Link to the free full text of the paper