© 2001 Macmillan Magazines Ltd490 | JULY 2001 | VOLUME 2 www.nature.com/reviews/molcellbio

H I G H L I G H T S

Wnt wonderlandWnt proteins — mediators ofcell–cell signalling — are inthe news again (see theHighlight on page 488) sowhat better place to expandyour knowledge than to visitthe Wnt homepage,launched and run by RoelNusse?

The homepage itself is wellpresented, beginning with ashort paragraph introducingthe Wnt proteins. This ispositioned above an overviewof the contents, which isfurther subdivided into colour-coded sections coveringdifferent components of theWnt signalling pathway —Wnts, Frizzled, axin anddishevelled, to name ahandful. Within each sectionyou can find information onspecies alignments, links toPubMed and clearlytabulated information aboutexpression patterns,chromosomal location. Forthose seeking structuralsatisfaction, regions of axin,dishevelled and β-catenin canbe viewed in threedimensions using the Cn3Dprogram (easily obtainablefrom NCBI by following thelinks). Another resource to beparticularly commended isthe ‘Wnt reagents andassays’ section, whichprovides invaluableinformation about sources ofWnt antibodies and proteins.Included in this section arestrategies for generatingantisera and advice on howbest to make bioactive Wntproteins.

As no signalling moleculehomepage would becomplete without a signallingcascade, it is reassuring tosee thumbnails on thehomepage, each of whichoffers the option of anattractive full-size diagram.Click on one of the proteinsand you instantly receive adeluge of information —perhaps even slightly visuallyoverwhelming. Overall, thesite provides extremelyrelevant links, includingupcoming meetings (whichare admirably up-to-date),reviews on Wnts and contactdetails of fellow Wnt workers.

Katrin Bussell

WEB WATCH

Understanding how hair follicles are formed and main-tained has always been a challenge, but recent findingsmight help get to the root of this. Reporting in Cell,Huelsken et al. have found that β-catenin has a dual role inhair follicle formation — first it mediates the formation ofhair placodes (the first indication of the site of the futurehair) during embryogenesis, and second it acts in the dif-ferentiation of adult skin cells.

After observing an increase in β-catenin messengerRNA expression in the epithelial part of developing hairplacodes, the authors studied the function of β-catenin inskin and hair development in more detail using Cre/loxtechnology to create a conditional mutant in which β-catenin expression could be specifically deleted from theskin. Although the resultant mutant mice were viable,patches of hairless skin were seen in eight-day-old mice.Over the next two weeks, the rest of the hair grew normally,but was then lost.

Closer inspection revealed the presence of extendedregions of β-catenin-negative epithelium that lacked hairplacodes in 15-day-old mutant mouse embryos, in con-trast to wild-type embryos, in which developing hair pla-codes expressed high levels of β-catenin. This implicatesβ-catenin in the formation of epithelial placodes. Duringthe active phase of the hair cycle (anagen) in wild-typemice, both hair follicle and epidermal keratinocytesexpress β-catenin. In the conditional-mutant mice, how-ever, both the upper part of hair follicles and the epider-mis were devoid of β-catenin. During the catagen(regression and shortening) and telogen (rest) phases ofthe hair cycle in the mutant mice, hair was subsequentlylost, hair canals widened and small cysts appeared. Nonew hair follicles formed, and the cysts grew and became

surrounded by a multilayered epithelium. It thereforeseems that cells from the hair-follicle-derived cysts havelost their follicular characteristics and show epidermaldifferentiation, implying that β-catenin is needed toinduce follicular differentiation.

One population of stem cells in the skin is known togive rise to keratinocyte precursors of the hair follicle andepidermis. So how does β-catenin influence the differentia-tion of these stem cells? And does it do this as a signallingor an adhesion molecule? In early embryos of β-catenin-deficient mice, plakoglobin (γ-catenin) is thought to com-pensate for the adhesive function of β-catenin.Plakoglobin, however, although present in the mutantmice, isn’t thought to compensate for β-catenin signallingin the skin.

Moreover, β-catenin deficiency had no effect on theexpression of tabby and downless — a ligand–receptor sys-tem that is crucial for early placode formation — butexpression of bone morphogenetic protein 2 (bmp2),bmp4 and bmp7 and sonic hedgehog (shh) was lost in theconditional mutants. β-catenin can therefore be placedgenetically downstream of tabby/downless in epithelialplacode formation, but upstream of bmp and shh. It isunclear whether β-catenin targets bmp and shh directly orindirectly, and one of the next challenges will be to under-stand how β-catenin signalling is coordinated with otherpathways involved in stem-cell differentiation.

Katrin Bussell

References and linksORIGINAL RESEARCH PAPER Huelsken, J. et al. β-catenin controls hairfollicle morphogenesis and stem cell differentation in the skin. Cell 104,533–545 (2001) FURTHER READING Oshima, H. et al. Morphogenesis and renewal of hairfollicles from adult multipotent stem cells. Cell 105, 233–245 (2001)

Hair today, gonetomorrow

D E V E LO P M E N T

Cancer cells can maintain theirtelomeres by reactivating telomeraseor using a poorly characterizedtelomerase-independentmechanism. Aylin Rizki and VickiLundblad now report in Nature thata familiar cause of cancer — lack ofmismatch repair — may contributeto this second mechanism.

One function of mismatch repair isto prevent recombination betweenimperfectly homologous sequences.As telomeres contain imperfectrepeats, the authors suspected that

mismatch repair might inhibitrecombination between telomeres.So, they compared the growth ratesof budding yeast lacking EST2 (est2-∆) — which encodes the proteincomponent of telomerase — withmutants lacking both EST2 and amismatch repair gene, MSH2. Asexpected, after about 100generations the growth rate of theest2-∆ mutants was severelyimpaired, but in the double mutantsthis phenotype was less pronounced.Mutations of other mismatch repair

genes also conferred a growthadvantage in an est2-∆ background,but the effect was reversed bydeletion of RAD52, a gene shownpreviously to promote arecombination-dependent pathwayfor telomere maintenance. Couldthe growth advantage simply be asecondary consequence ofmutations caused by defective DNArepair? This is unlikely becauseintroduction of a DNA polymerasemutation that generates mutationsat a similar rate to mismatch repairmutants didn’t provide a growthadvantage.

Are these results relevant to cancer?The authors introduced twodifferent missense mutations into

Mismatch repair comes to an end

T E LO M E R E S