584 | AUGUST 2002 | VOLUME 3 www.nature.com/reviews/neuro

Nogo and myelin-associ-ated glycoprotein (MAG) —

two myelin proteins thatlimit axon regeneration —

have received attention as possible therapeutictargets after spinal cordinjury. The action ofNogo depends on itsaxonal receptor, NgR. Bycontrast, the identity ofthe MAG receptor hasremained a mystery. NowDomeniconi et al. andLiu et al. report thatMAG also binds toNgR, and that thisinteraction mediatesits inhibitory effecton axon outgrowth.

The two studiesshow that MAG and

NgR interact directly

and that disrupting this interaction preventsMAG from inhibiting axonal growth. In addi-tion, Liu et al. found that expressing NgRconferred MAG sensitivity on otherwiseinsensitive neurons.

Although the findings from both groupsagree in general terms, they differ in oneimportant respect; whereas Domeniconi et al.found that Nogo and MAG compete for thesame site on NgR, Liu et al. obtained evidencefor independent binding sites on the receptor.It will be important to resolve this difference,as the existence of more than one binding sitemight have implications for the design ofmolecules that aim to block the inhibitoryaction of NgR.

Meanwhile, a third paper reports on yetanother protein that binds to NgR — oligo-dendrocyte-myelin glycoprotein (OMgp).Wang et al. showed that this previously identi-fied protein also inhibits neurite outgrowth ina NgR-dependent way, and that receptorexpression confers OMgp responsiveness on

insensitive neurons. Moreover,Wang et al. foundthat OMgp and Nogo bind to overlapping siteson NgR.

So, three myelin proteins that inhibit axonoutgrowth share the same receptor. This factcompels us to take a closer look at the intra-cellular processes downstream of NgR.Intriguingly, the inhibitory effect of myelin isblocked if the small GTPase Rho is inactivatedor if cyclic AMP is elevated, pointing to thesesignalling molecules as possible transducers ofthe NgR signal. However, NgR is not a trans-membrane protein; it is anchored to the mem-brane by a glycosylphosphatidylinositol link.So, how is the binding of Nogo, MAG andOMpg transduced to the inside of the cell? We still need to discover further molecules that interact with the receptor, linking it to itsintracellular signalling pathways.

Juan Carlos López

References and linksORIGINAL RESEARCH PAPERSLiu, B. P. et al. Myelin-associated glycoprotein as a functionalligand for the Nogo-66 receptor. Science 27 June 2002(doi:0.1126/science.1073031) | Domeniconi, M. et al. Myelin-associated glycoprotein interacts with the Nogo66 receptor toinhibit neurite outgrowth. Neuron 28 June 2002(doi:10.1016/S0896627302007705) | Wang, K. C et al.Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligandthat inhibits neurite outgrowth. Nature 16 June 2002(doi:10.1038/nature00867)

The Smads are a family of proteins withfunctions that include the transduction ofsignalling by the transforming growth factor-βsuperfamily, which includes the bonemorphogenetic proteins (BMPs).In Developmental Cell, LeSueur et al. reportthat Smad10, a newly identified Smad inXenopus, is essential for the formation ofthe frog nervous system.

Smad10 seems to belong to the class ofmolecules known as common Smads (co-Smads), which associate with receptor-regulated Smads (R-Smads). These, in turn,interact directly with TGF-β ligand–receptorcomplexes. The only other known co-Smad isSmad4, which is structurally very similar toSmad10. To analyse the function of Smad10, theauthors used two loss-of-function approaches— they injected Xenopus embryos with adominant-negative form of Smad10 or with anantisense oligonucleotide. In both cases, theembryos failed to develop a neural tube.

LeSueur et al. then tested the effects ofSmad10 inhibition on the activity of twoneural inducers — fibroblast growth factor

(FGF), which induces posterior neural tissue,and the BMP inhibitor noggin, which inducesanterior neural tissue — in uncommittedectodermal tissue explants. They found thatinhibiting Smad10 prevented the activation ofposterior neural markers by FGF, and ofanterior neural markers by noggin. So,Smad10 is required for the induction of bothanterior and posterior neural tissue, bymediating FGF and noggin activity,respectively. The mechanism that isresponsible for this dual response has not beenfully elucidated, although initial findingsindicate that the phosphorylation state ofSmad10 is a key factor.

The implications of these findings for otherspecies are not yet known, and no Smad10homologue has been identified in the mouse orthe chick. However, previous studies in miceindicated that Smad4 might not be the onlymolecule with co-Smad activity, so it isexpected that molecules that are functionally— if not structurally — equivalent are waitingto be discovered.

Heather Wood

References and linksORIGINAL RESEARCH PAPER LeSueur, J. A. et al. Smad10is required for formation of the frog nervous system. Dev. Cell 2,771–783 (2002)FURTHER READING Muñoz-Sanjuán, I. & Brivanlou, A. H.Neural induction, the default model and embryonic stem cells.Nature Rev. Neurosci. 3, 271–280 (2002)

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