© 2003 Nature Publishing Group

244 | APRIL 2003 | VOLUME 4 www.nature.com/reviews/neuro

H I G H L I G H T S

It is possible to dissociate the roleof oligodendrocytes in myelinationfrom their involvement in axonalsupport, according to new researchpublished in Nature Genetics.Traditionally, both functions havebeen thought to be concurrent, butthe study of Lappe-Siefke et al.shows that knocking out the Cnp1gene in mice leads to axonal losswithout any apparent effect onmyelin structure.

Cnp1 encodes a cyclic-nucleotidephosphodiesterase (CNP) that

seems to participate in RNAmetabolism. Although CNP ispresent in oligodendrocytes andSchwann cells, its function in thenervous system is unknown. Theauthors knocked out the Cnp1gene and failed to see anysignificant alteration in thebiochemical and structuralproperties of myelin. However,the mutant mice developedprogressive motor deficits anddied prematurely. Moreimportantly, the brains of theCnp1–/– mice showed marked signsof degeneration that seemed toaffect neurons more profoundlythan oligodendrocytes. Inparticular, Lappe-Siefke et al.observed profuse axonal swellingthat did not result from alterationsof the integrity of myelin.

How CNP participates in theregulation of axonal survivalremains an enigma and should bethe focus of subsequent studies.But more importantly, theseobservations indicate that the two main functions ofoligodendrocytes can beseparated, and establish a doubledissociation between them.So, mutations in the gene thatencodes the myelin basic proteingive rise to the shiverer phenotypeand are associated with severedemyelination but normal axonal structure.

Juan Carlos López

References and linksORIGINAL RESEARCH PAPER Lappe-Siefke, C. et al. Disruption of Cnp1 uncouplesoligodendroglial functions in axonal supportand myelination. Nature Genet. 18 February2003 (doi:10.1038/ng1095)

Indeed, the behaviour of Vamp2 isconsistent with such a model.Sampo et al. showed that mutationof the Vamp2 endocytosis signalabolished the polarized distributionof this protein, resulting in equaldistribution between axonal anddendritic membrane domains.

By contrast, removal of theNgCAM endocytosis signal had noeffect on the subcellular distributionof this protein. However, the authorsfound that if they removed a seriesof fibronectin type III-like (FnIII)repeats from the extracellulardomain of NgCAM, the moleculecould now be incorporated into thedendritic membrane. Furthermore,addition of these repeats to a closelyrelated protein, NrCAM, which doesnot normally have a polarized distri-bution, caused this molecule to bedirected preferentially to the axonalmembrane. This indicates that theFnIII repeats are both necessary and

The generation and maintenance ofneuronal polarity depends on thedifferential distribution of key pro-teins to the axonal or dendritic com-partment. This could be achieved inat least two ways — proteins mightbe specifically targeted to certainprojections (‘selective delivery’), orthey might initially be distributedmore evenly through the cell andsubsequently become eliminatedfrom certain regions (‘selectiveretention’). In a new paper in Neuron,Sampo et al. show that both of thesesystems operate in neurons, and thatdifferent mechanisms are employedby different proteins.

The neuronal membrane pro-teins vesicle-associated membraneprotein 2 (Vamp2) and neuron-gliacell adhesion molecule (NgCAM)are both preferentially localized tothe axon. Both proteins are trans-ported into dendrites, but very littleVamp2 or NgCAM are detected onthe dendritic membrane. Each pro-tein contains an intracellular signalsequence that enables them toundergo endocytosis, so both couldpotentially be internalized afterdelivery to the dendritic membrane.

I’m sticking with youOne story that seems to hitthe headlines fairly regularly isthe continuing investigationinto ‘stuck-tune syndrome’— that infuriating conditionwhere you can’t get a certaintune out of your head. Justwhen we thought that thestory had finally exhausted itsnews potential, a group inCincinnati has come up withyet another take on thephenomenon.

It seems that people withneurotic tendencies — as ifthey didn’t have enough toworry about — are morelikely to be plagued by astuck tune than those of amore easy-going disposition.However, researcher JamesKellaris reassures us thatthese people “are notseriously neurotic, but maysimply be more prone toworrying and anxiety, andmay have neurotic habits likebiting pencils or tappingfingernails” (Reuters, USA,24 February 2003).

Health web site WebMDprovides a top 10 of themost commonly stucktunes, presumably to helptheir readers to empathizewith sufferers. Among theoffenders in this hellish hitparade are ‘Who let thedogs out’, the ‘MissionImpossible’ theme and‘YMCA’. The main criteria for‘sticky’ tunes are that theyare “relatively simple,repetitive, and contain anelement that surprises thelistener” (Reuters). Kellarisalso found that stupid lyricscould contribute significantlyto a song’s adhesiveproperties.

So, what’s the cure? Onecommon strategy is to try toreplace the stuck tune witha more agreeable melody.Alternatively, Kellaris foundthat “sometimes it helps tosing through the entiresong” (Reuters), and somepeople even insist thatchewing a cinnamon stickcan help them to dislodge astuck tune. If all else fails,the only option might be toavoid listening to musicaltogether until the problemgoes away.

Heather Wood

IN THE NEWS

A surprisingseparation

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sufficient to ensure that NgCAM istargeted specifically to the axon.

In summary, these findings pro-vide compelling evidence that Vamp2is eliminated from the dendriticmembrane by selective retention,whereas carriers containing NgCAMare prevented from fusing with the dendritic plasma membrane.Sampo et al. propose that VAMP2and NgCAM are transported aroundthe cell by different carrier vesicles,but further experiments will berequired to confirm this idea. Theanswer to this and other questionsshould provide us with some impor-tant new insights into the molecularand cellular mechanisms that underlieneuronal polarity.

Heather WoodReferences and links

ORIGINAL RESEARCH PAPER Sampo, B. et al.Two distinct mechanisms target membrane proteinsto the axonal surface. Neuron 37, 611–624 (2003)WEB SITEGary Banker’s laboratory: http://www.ohsu.edu/croet/faculty/banker/bankerlab.html

Poles apart

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