establishment of the apical plasma membranedomain in epithelial cells. J. Cell Biol. 107,1717–1728.

3. Yamada, S., Pokutta, S., Drees, F., Weis, W.I.,and Nelson, W.J. (2005). Deconstructing thecadherin-catenin-actin complex. Cell 123,889–901.

4. Shen, L., Weber, C.R., and Turner, J.R. (2008).The tight junction protein complex undergoesrapid and continuous molecular remodeling atsteady state. J. Cell Biol. 181, 683–695.

5. Akhtar, N., and Hotchin, N.A. (2001). RAC1regulates adherens junctions throughendocytosis of E-cadherin. Mol. Biol. Cell 12,847–862.

6. Georgiou, M., Marinari, E., Burden, J., andBaum, B. (2008). Cdc42, Par6 and aPKCregulate Arp2/3-mediated endocytosis tocontrol local adherens junction stability. Curr.Biol. 18, 1631–1638.

7. Leibfried, A., Fricke, R., Morgan, M.J.,Bogdan, S., and Bellaiche, Y. (2008).Drosophila Cip4 and WASp define a branchof the Cdc42-Par6-aPKC pathway regulatingE-Cadherin endocytosis. Curr. Biol. 18,1639–1648.

8. Hurd, T.W., Gao, L., Roh, M.H., Macara, I.G., andMargolis, B. (2003). Direct interaction of twopolarity complexes implicated in epithelial tightjunction assembly. Nat. Cell Biol. 5, 137–142.

9. Harris, T.J., and Peifer, M. (2005). Thepositioning and segregation of apical cuesduring epithelial polarity establishment inDrosophila. J. Cell Biol. 170, 813–823.

10. Pilot, F., Philippe, J.M., Lemmers, C., andLecuit, T. (2006). Spatial control of actinorganization at adherens junctions bya synaptotagmin-like protein Btsz. Nature 442,580–584.

11. Izumi, G., Sakisaka, T., Baba, T., Tanaka, S.,Morimoto, K., and Takai, Y. (2004). Endocytosisof E-cadherin regulated by Rac and Cdc42small G proteins through IQGAP1 and actinfilaments. J. Cell Biol. 166, 237–248.

12. Balklava, Z., Pant, S., Fares, H., and Grant, B.D.(2007). Genome-wide analysis identifiesa general requirement for polarity proteinsin endocytic traffic. Nat. Cell Biol. 9,1066–1073.

13. Wells, C.D., Fawcett, J.P., Traweger, A.,Yamanaka, Y., Goudreault, M., Elder, K.,Kulkarni, S., Gish, G., Virag, C., Lim, C., et al.(2006). A Rich1/Amot complex regulates theCdc42 GTPase and apical-polarity proteinsin epithelial cells. Cell 125, 535–548.

14. Otani, T., Ichii, T., Aono, S., and Takeichi, M.(2006). Cdc42 GEF Tuba regulates thejunctional configuration of simple epithelialcells. J. Cell Biol. 175, 135–146.

15. Shen, Y., Hirsch, D.S., Sasiela, C.A., andWu, W.J. (2008). Cdc42 regulates E-cadherinubiquitination and degradation through anepidermal growth factor receptor toSrc-mediated pathway. J. Biol. Chem. 283,5127–5137.

16. Troyanovsky, R.B., Sokolov, E.P., andTroyanovsky, S.M. (2006). Endocytosis ofcadherin from intracellular junctions is the

driving force for cadherin adhesive dimerdisassembly. Mol. Biol. Cell 17, 3484–3493.

17. Coyne, C.B., Shen, L., Turner, J.R., andBergelson, J.M. (2007). Coxsackievirus entryacross epithelial tight junctions requiresoccludin and the small GTPases Rab34 andRab5. Cell Host Microbe 2, 181–192.

18. Mengaud, J., Ohayon, H., Gounon, P.,Mege, R.M., and Cossart, P. (1996). E-cadherinis the receptor for internalin, a surface proteinrequired for entry of L. monocytogenes intoepithelial cells. Cell 84, 923–932.

19. Clayburgh, D.R., Barrett, T.A., Tang, Y.,Meddings, J.B., Van Eldik, L.J.,Watterson, D.M., Clarke, L.L., Mrsny, R.J., andTurner, J.R. (2005). Epithelial myosin light chainkinase-dependent barrier dysfunction mediatesT cell activation-induced diarrhea in vivo. J.Clin. Invest. 115, 2702–2715.

20. Schwarz, B.T., Wang, F., Shen, L.,Clayburgh, D.R., Su, L., Wang, Y., Fu, Y.X., andTurner, J.R. (2007). LIGHT signals directlyto intestinal epithelia to cause barrierdysfunction via cytoskeletal and endocyticmechanisms. Gastroenterology 132,2383–2394.

Department of Pathology, University ofChicago, Chicago, IL 60637, USA.*E-mail: jturner@bsd.uchicago.edu

DOI: 10.1016/j.cub.2008.10.010

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Evolutionary Biology: PatchyFood May Maintain a ForagingPolymorphism

Two naturally-occurring alleles in the nematode Caenorhabditis elegans thatdiffer by a single amino acid and cause striking differences in foraging behaviorare probably maintained by selection in patchy environments.

Karin Kiontke

One major question of evolutionarybiology is how genetic diversity ismaintained in natural populations.Darwin figured that natural selectioncould not only explain how new adaptivevariants replace old, less-adaptivevariants, but also how different variantscan coexist if, for example, the variantsallowed different resources to be used.Finches with bigger beaks could crackbigger seeds, reducing competition withsmaller-beaked ones. Darwin thoughtthis ‘divergence of character’ couldexplain speciation. Since Darwin,mathematical models which describehow evolution could shape geneticvariation have multiplied. Density- andfrequency-dependent selection,heterozygote advantage, resourcepartitioning and environmentalheterogeneity have all been suggestedas mechanism that maintain variation

[1]. But it is rare to find a systemthat is amenable to controlledexperimental studies and in whichthe genetic basis of natural variationis known — especially one affectinga clearly adaptive behavior such asforaging.

Two examples of such variationhave been described in two of ourbest-known model organisms: thesolitary versus gregariouspolymorphism in the nematodeCaenorhabditis elegans; and thesitter versus rover polymorphism inthe fruit fly Drosophila melanogaster.Both of these polymorphisms influencehow the animals forage for food,occur in nature and depend on allelicdifferences in a single gene. Howthese polymorphisms are maintainedhas puzzled researchers for years.In this issue of Current Biology,Gloria-Soria and Azevedo [2] reportnew data suggesting that the

foraging polymorphism in C. elegansis maintained by a trade-offbetween dispersal propensity andcompetitive ability in a fragmentedenvironment.

Natural isolates of C. elegans differin their behavior on food, which inthe laboratory is a lawn of Escherichiacoli in a Petri dish. Animals from thestandard laboratory strain N2 foragealone and over the entire surface ofthe food patch — ‘solitary’ behavior.Animals from other strains forage atthe thick border of the bacterial lawn anddo so in groups — ‘gregarious’ behavior[3]. This behavioral difference dependson a single amino acid difference in theG-protein-coupled receptor NPR-1 [4].Along with the solitary versus gregariousfeeding behavior, the npr-1polymorphism influences a host of otherphenotypes: gregarious animals movefaster on food and tend to bury into theagar of their plate [3]; they are betterat avoiding hyperoxia [5]; and they adaptfaster to elevated ethanolconcentrations [6] than solitaryworms.

Gloria-Soria and Azevedo [2] havediscovered that this polymorphism alsoinfluences short-distance dispersalin a fragmented food environment,adding an important piece to thepuzzle of how this polymorphismevolved. When placed in the middle

Current Biology Vol 18 No 21R1018

of a plate with 12 food patches inthree concentric rings, worms with thesolitary npr-1 allele stayed in the foodclosest to the middle, whereas mostworms with the gregarious alleleventured to the outer food patches. Thisdifference in dispersal propensity is alsoseen in experiments with single worms,which are more likely to leave a foodpatch when they carry the gregariousallele. The authors also found thatsolitary and gregarious worms canpartition a continuous food resource.They showed this in a clever experimentwith GFP-labeled E. coli whichallowed them to visualize the effectof worm grazing on the bacteriallawn. As expected, fluorescence ofthe food is reduced predominately at theborder of the lawn when gregariousworms feed on the bacteria; but thefluorescence declines throughout thelawn when a solitary strain is tested.When the two strains were mixed atvarious proportions, this difference inforaging sites was maintained.

The foraging polymorphism inD. melanogaster resembles the npr-1polymorphism of C. elegans in severalaspects: ‘rover’ larvae with a forR

allele move more when feeding andthus leave longer foraging trails ona yeast-covered Petri dish than ‘sitter’larvae carrying the fors allele [7]. Also,in a patchy food environment, roverlarvae move significantly more fromfood patch to food patch than sitters[8]. As with the C. elegans foragingbehavior polymorphism, thesedifferences are only apparent whenfood is present. The foragingpolymorphism in D. melanogaster iscaused by variation in a single genewhich encodes a cGMP-dependentprotein kinase [9].

Natural populations ofD. melanogaster comprise 70%sitters and 30% rovers (references in[7]). A recent study [10] concludedthat this polymorphism is maintainedby negative frequency-dependentselection, although allele frequency isalso influenced by density-dependentselection during the larval stage [11].Under laboratory conditions withlow food abundance, each morphhas a higher fitness when it is rare.When food is abundant, the sittermorph shows higher fitness.Heterozygote advantage did notappear to play a role [10].

To date, we know much less aboutnatural polymorphisms in C. elegans.Only two alleles of npr-1 were found

among 17 C. elegans isolates fromacross the globe [4]. Thus, theexistence of these two alleles mustpredate the global expansion of theC. elegans range and should thereforebe old. Evidence that both allelesoccur together in the same populationis still scant, but on two occasions,gregarious and solitary worms werefound in the same sample or in thesame location at different times(references in [2]). Experiments witha GFP-marked solitary strain anda gregarious wild isolate found noevidence that either density- orfrequency-dependent selectionmaintains this polymorphism inC. elegans [12].

Although solitary and gregariousworms can partition a continuousfood source, this is not sufficient toallow coexistence. In competitionexperiments with a continuous foodsource, worms with the solitary alleleof npr-1 had higher fitness thanworms with the gregarious allele inthe same genetic background [2].But when the food environment wasfragmented — with several foodpatches present — the two strainsperformed equally well. Thus, bothalleles should be able to coexist innature provided their habitat ispatchy, unlike the uniform bacteriallawn on a laboratory Petri dish.

Until recently, very little was knowabout the natural habitat of C. elegans.In the last few years, we have learnedthat C. elegans prefers bacteria-richhabitats such as compost or gardensoil. Even in compost samples,however, most C. elegans individualswere found as dauer larvae [13], analternative third juvenile stage whichis resistant to many stresses, arrestsits development and does not feed[14]. Under which natural conditionsC. elegans reproduces remaineduncertain. Lately, populations withfeeding larvae and adults of C. elegansand other Caenorhabditis specieswere repeatedly isolated from rottingfruit ([15] and M. Alion, M-A. Felixand M. Rockman, personalcommunication). It is increasinglyclear that C. elegans shares its habitatwith fruit flies and is not a soilnematode but a fruit-worm. It isthus likely that the natural habitat ofC. elegans is temporary, rapidlychanging and patchily distributedlike those of D. melanogaster and ofmany nematode species related toC. elegans [16–18].

Conditions are unlikely to beuniform across a food resource, andthe conditions under which thegregarious and solitary morphs cancoexist should be common. Theserecent advances in understandingC. elegans ecology should greatlyhelp us to understand the biologicalrelevance and evolution of the foragingpolymorphism in this species. Forinstance, it is now possible to samplesufficiently large reproducingpopulations of C. elegans to assessthe frequency of the two alleles ineach population. It should also bepossible to follow the colonization ofa food resource under more naturalconditions, and to study the role ofshort-distance dispersal. Adaptationto high ethanol concentrations, alsoinfluenced by npr-1, gains a differentimportance in a habitat full of yeastslike a rotting apple or peach. Finally, itis quite possible that the similaritiesbetween the foraging polymorphismsin C. elegans and D. melanogasterare not mere coincidences butevolved as a reaction to similar habitatproperties.

References1. Clarke, B.C. (1979). The evolution of genetic

diversity. Proc. R. Soc. Lond. B 205,453–474.

2. Gloria-Soria, A., and Azevedo, R.B. (2008).npr-1 regulates foraging and dispersalstrategies in Caenorhabditis elegans. Curr.Biol. 18, 1694–1699.

3. Hodgkin, J., and Doniach, T. (1997). Naturalvariation and copulatory plug formation inCaenorhabditis elegans. Genetics 146,149–164.

4. de Bono, M., and Bargmann, C.I. (1998).Natural variation in a neuropeptide Yreceptor homolog modifies social behaviorand food response in C. elegans. Cell 94,679–689.

5. Gray, J.M., Karow, D.S., Lu, H., Chang, A.J.,Chang, J.S., Ellis, R.E., Marletta, M.A., andBargmann, C.I. (2004). Oxygen sensation andsocial feeding mediated by a C. elegansguanylate cyclase homologue. Nature 430,317–322.

6. Davies, A.G., Bettinger, J.C., Thiele, T.R.,Judy, M.E., and McIntire, S.L. (2004). Naturalvariation in the npr-1 gene modifies ethanolresponses of wild strains of C. elegans. Neuron42, 731–743.

7. Sokolowski, M.B. (2001). Drosophila: Geneticsmeets behaviour. Nat. Rev. Genet. 2, 879–890.

8. Sokolowski, M.B., Hansell, R.I., and Rotin, D.(1983). Drosophila larval foraging behavior. II.Selection in the sibling species,D. melanogaster and D. simulans. Behav.Genet. 13, 169–177.

9. Osborne, K.A., Robichon, A., Burgess, E.,Butland, S., Shaw, R.A., Coulthard, A.,Pereira, H.S., Greenspan, R.J., andSokolowski, M.B. (1997). Natural behaviorpolymorphism due to a cGMP-dependentprotein kinase of Drosophila. Science 277,834–836.

10. Fitzpatrick, M.J., Feder, E., Rowe, L., andSokolowski, M.B. (2007). Maintaininga behaviour polymorphism by frequency-dependent selection on a single gene. Nature447, 210–212.

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11. Sokolowski, M.B., Pereira, H.S., and Hughes, K.(1997). Evolution of foraging behavior inDrosophila by density-dependent selection.Proc. Natl. Acad. Sci. USA 94, 7373–7377.

12. Dennehy, J.J., and Livdahl, T.P. (2004).Polymorphic foraging behavior amongCaenorhabditis elegans: Frequency- anddensity-dependent selection. J. Nematol. 36,276–280.

13. Barriere, A., and Felix, M.A. (2005). High localgenetic diversity and low outcrossing rate inCaenorhabditis elegans natural populations.Curr. Biol. 15, 1176–1184.

Protein Quality ConOther JUNQ

The accumulation of misfolded cytosolto cellular stress. To protect the cell, dactively sequestered in two newly discJUNQ and IPOD, which are highly cons

Katrin Bagola and Thomas Sommer

Quality control systems monitorthe correct folding, assembly andfunctionality of cellular proteins.Proteins that are singled out by thesesystems generally exhibit alteredfunctions and tend to form aggregates.Cells have developed differentstrategies to cope with defectiveproteins: if possible, chaperonesrefold aberrant proteins to restore theirnative conformation [1], but, if theseunwanted proteins cannot be repaired,they are rapidly destroyed by theubiquitin–proteasome pathway [2,3].Defects in the breakdown ofaberrant polypeptides may resultin their aggregation. Formationof aggregates is tightly linked toseveral neurodegenerative disorderscollectively termed ‘protein foldingdiseases’. Current studies, however,suggest that the cellular toxicity isassociated with non-native solubleprotein oligomers and that theformation of large aggregates isinstead cytoprotective [4].

In a recent study aimed at gaininga better understanding of themechanisms that lead to theformation of protein aggregates,Kaganovich et al. [5] found that anincreased incidence of misfoldedproteins led to their accumulation intwo distinct subcellular compartmentsin both yeast and mammalian cells.Kaganovich et al. expressedaggregation-prone proteins as wellas substrates that were unable to

14. Wood, W. (1988). The Nematode Caenorhabditiselegans (Cold Spring Harbor, New York: ColdSpring Harbor Laboratory Press).

15. Barriere, A., and Felix, M.A. (2007). Temporaldynamics and linkage disequilibrium in naturalCaenorhabditis elegans populations. Genetics176, 999–1011.

16. Keller, A. (2007). Drosophila melanogaster’shistory as a human commensal. Curr. Biol. 17,R77–R81.

17. Reaume, C.J., and Sokolowski, M.B. (2006).The nature of Drosophila melanogaster. Curr.Biol. 16, R623–R628.

trol: On IPODs and

ic or aggregation-prone proteins leadsamaged or aggregated proteins areovered quality control compartments,erved in evolution.

mature properly due to differentdefects: in the case of Ubc9ts

misfolding is triggered by a thermalshift, whereas the actin E364K mutantfails to fold as a result of the pointmutation. Another substrate testedwas the von Hippel-Lindau proteinVHL, which is expressed in theabsence of partner proteins.Under stress conditions,immunofluorescence analysisrevealed the formation of two distinctinclusions. Firstly, a juxtanuclearinclusion was formed as aconsequence of proteinoverexpression or proteasomeinhibition. Additional stress, likeelevated temperature, then led tothe development of a second,large perivacuolar inclusion at thecell periphery. Most interestingly,all disease-related amyloidogenicproteins Kaganovich et al. [5] tested(Rnq1, Ure2, and the disease-relatedHuntingtin mutant HttQ103, whichcontains an extended polyglutaminestretch) form an aggregatethat exclusively colocalized with aperivacuolar peripheral compartment,without showing any colocalizationwith the juxtanuclear inclusion.In contrast to misfolded cytosolicproteins, aggregation of amyloidogenicproteins in the perivacuolarcompartment occurred even inunstressed cells. These findingsindicate that different classes ofdefective proteins are sequesteredin distinct inclusions. Given thatboth newly discovered compartments

18. Kiontke, K., and Sudhaus, W., (2006). Ecologyof Caenorhabditis species. In WormBook,The C. elegans Research Community, ed.doi/10.1895/wormbook.1.37.1,http://www.wormbook.org.

Department of Biology, New York University,New York, NY 10003, USA.E-mail: kk52@nyu.edu

DOI: 10.1016/j.cub.2008.09.017

can be found in yeast and mammaliancells, these inclusions thus seem tobe evolutionarily conserved.

The ensuing analysis of theprotein diffusion kinetics betweenthe two quality control compartmentsand the cytoplasm revealed that thejuxtanuclear inclusion largely harborsmisfolded but soluble proteins that canexchange with the cytoplasmic pool.Therefore, this compartment is called‘juxtanuclear quality control’ or JUNQ.In contrast, results for the perivacuolarperipheral compartment led to thesuggestion that this inclusion containsmostly non-diffusing and probablyaggregated substrates, which leadsto its designation as ‘insolubleprotein deposit’ or IPOD.

Interestingly, the two compartmentshave similarities regarding theirdevelopment and function. Theformation of both JUNQ and IPODwas found to depend on the formationof microtubules. Benomyl, a drug thatdepolymerizes microtubules, led tosubstrate accumulation in small punctathroughout the cytosol. This impliesthat both JUNQ and IPOD areformed by an active mechanismthat requires the cellular transportmachinery. The proposed functionof both compartments as qualitycontrol compartments implies thatmolecular chaperones contribute tothe formation of JUNQ and IPODand in the partitioning of substrateproteins to these compartments.Indeed, the cytosolic chaperoneHsp104, which interacts with misfoldedor aggregated proteins, colocalizeswith both compartments where itmay assist in solubilizing aggregatedproteins to allow either theirdegradation or refolding [6]. Itshould be noted, however, that severalin vitro studies demonstrated thatHsp104 can fulfill its function only incooperation with Hsp70 [7–9]. Thus,it remains to be shown whether