H I G H L I G H T S

NATURE REVIEWS | NEUROSCIENCE VOLUME 5 | MAY 2004 | 343

There is a precise and predictable relationshipbetween the diameter of an axon and thethickness of the myelin that surrounds it. Writingin Science, Michailov, Sereda and colleaguesdescribe evidence that the amount of neuregulin-1(Nrg1) that is produced by an axon tells Schwanncells how thick the myelin sheath around thataxon should be.

The speed at which action potentials areconducted along an axon depends largely on thediameter of the axon and the thickness of itsmyelin sheath — two factors that are closelyrelated. Maintaining the precise control ofconductance velocity is essential for the properfunction of the nervous system, and it has beensuggested that myelin thickness might becontrolled by interactions between ligandsproduced by the axon and receptors on themyelinating glia. Michailov et al. tested the ideathat the axonal ligand that is responsible — in theperiphery, at least — is Nrg1, interacting withErbB receptors on Schwann cells.

The Nrg1 gene is expressed in neurons of thesciatic nerve in mice, and ErbB2 and ErbB3 areexpressed by Schwann cells. If interactionsbetween Nrg1 and ErbB receptors control myelinthickness, changes in the amount of ligand orreceptor might alter the thickness of the myelinsheath. When the authors generated compoundheterozygote mice that had reduced gene dosagesof both Nrg1 and ErbB2, they found that themyelin in the sciatic nerves of the mice wassignificantly thinner than usual. Although themice seemed normal, the conduction velocity intheir nerves was also reduced, even though thesizes of the axons were unchanged.

To narrow down the cause of the reducedmyelination, the authors looked at mice withreduced dosages of just the Nrg1 gene or the ErbB2gene. Mice that were heterozygous for ErbB2showed normal myelination, but in the Nrg1heterozygotes, the myelin was as thin as in thecompound heterozygotes. So the expression ofNrg1 seems to control the thickness of myelin.

To test this theory further, the authorsgenerated mice in which Nrg1 was overexpressedunder the control of the murine Thy1.2 promotor,so that the excess Nrg1 was expressed specificallyin post-natal motor neurons and dorsal rootganglion neurons. In these mice, the peripheralnerves showed hypermyelination when comparedwith wild-type mice.

There are three isoforms of Nrg1, and theseeffects seem to be specific for Nrg1 type III. Micethat overexpressed Nrg1 type III showed

hypermyelination, but mice that overexpressedNrg1 type I did not (although they did show somemyelin abnormalities in the CNS). A specificreduction in the expression of the Nrg1 type IIIisoform also produced hypomyelination,indicating that Nrg1 types I and II cannotcompensate for the lack of the type III isoform.

These results support a model in which Nrg1type III is produced as a function of axonaldiameter. The amount of Nrg1 dictates theamount of signalling through the Schwann cellErbB receptors, and this controls the degree ofmyelination of each axon. Important questionsinclude how the production of Nrg1 isquantitatively controlled, and what signallingpathway is responsible for dictating myelinthickness as a result.

Rachel Jones

References and linksORIGINAL RESEARCH PAPER Michailov, G. V. et al. Axonalneuregulin-1 regulates myelin sheath thickness. Science 25 March2004 (10.1126/science.1095862)WEB SITENave laboratory: http://nave.em.mpg.de/root/

Myelin made to measure

G L I Adopamine that was released in thenucleus accumbens in response tomorphine was greatly reduced, andinjection of plasmin into the nucleusaccumbens in tPA–/– mice reversedthis effect.

So, the authors propose that morphine causes an increase in tPAin the nucleus accumbens, whichconverts plasminogen to plasmin andthereby leads to an increase in therelease of dopamine. The pathwaythat leads from plasmin productionto dopamine release is unknown, butit could be related to the degradationof laminin (an extracellular matrixprotein that regulates calcium chan-nels at synapses) by plasmin. Futurework should focus on elucidatingthis pathway.

Rachel Jones

References and linksORIGINAL RESEARCH PAPER Nagai, T. et al.The tissue plasminogen activator–plasmin systemparticipates in the rewarding effect of morphine byregulating dopamine release. Proc. Natl Acad. Sci.USA 101, 3650–3655 (2004)FURTHER READING Dityatev, A. & Schachner, M.Extracellular matrix molecules and synapticplasticity. Nature Rev. Neurosci. 4, 456–468 (2003)

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