previous study — and the choicebetween two larger stones — allcapuchins again chose correctly.Critically, in all of these studies, thesubjects had to evaluate the propertiesof the stone by interacting with it,typically by moving it, lifting it, ortapping it, because visual cues wereno longer informative. Thus, thesecapuchins did not simply learn throughtrial-and-error to identify stones ofcertain mineral composition or size, butappeared to understand that the mostimportant characteristic of the hammerstone was weight, and evaluated theirchoices accordingly.

This paper [1] adds two interestingangles to the literature. First, this abilitywas demonstrated in a species whichwas initially believed not to regularlyuse tools, based on experimentalstudies [2]. This reiterates theimportance of investigating behaviorsacross multiple studies, as well as theimportance of providing the animalswith sufficient experience andenrichment for these sorts of abilities toemerge. Second, the authors providesound evidence that animals use morethan just past experience to evaluateobjects, and actually understand the

critical characteristics relating to thetask at hand. This implies that thesemonkeys, and quite possibly otherspecies, are far more discerning thanpreviously believed. It will beinteresting to see whether futurestudies find this same discrimination inother tasks and among other species.Such knowledge will help to clarify theconditions which lead to theemergence of an understanding ofcomplex tasks in animals.

References1. Visalberghi, E., Addessi, E., Truppa, V.,

Spagnoletti, N., Ottoni, E., Izar, P., andFragaszy, D. (2009). Selection ofeffective stone tools by wild beardedcapuchin monkeys. Curr. Biol. 19,213–217.

2. Visalberghi, E. (1987). Acquisition ofnut-cracking behaviour by 2 capuchin monkeys(Cebus apella). Folia Primatol. 49, 168–181.

3. Boesch, C., and Boesch, H. (1983).Optimisation of nut-cracking with naturalhammers by wild chimpanzees. Behavior 83,265–286.

4. Mendes, N., Hanus, D., and Call, J. (2007).Raising the level: orangutans use water asa tool. Biol. Lett. 3, 453–455.

5. Dufour, V., and Sterck, E.H.M. (2008).Chimpanzees fail to plan in an exchange taskbut succeed in a tool-using procedure. Behav.Process 79, 19–27.

6. Mulcahy, N.J., and Call, J. (2006). Apes savetools for future use. Science 312, 1038–1040.

7. Boesch, C., and Boesch, Hedwige (1990). Tooluse and tool making in wild chimpanzees. FoliaPrimatol. 54, 86–99.

8. Lonsdorf, E.V. (2005). Sex differences in thedevelopment of termite-fishing skills in wildchimpanzees (Pan troglodytes schweinfurthii)of Gombe National Park, Tanzania. Anim.Behav. 70, 673–683.

9. Ottoni, E.B., and Mannu, M. (2001). Semi-freeranging tufted capuchin monkeys (Cebusapella) spontaneously use tools to crack opennuts. Int. J. Primatol. 22, 347–358.

10. Tanaka, I., Tokida, E., Takefushi, H., andHagiwara, T. (2001). Tube test in free-rangingJapanese macaques: use of sticks and stones

to obtain fruit from a transparent pipe. InPrimate Origins of Human Cognition andBehavior, T. Matsuzawa, ed. (Hong Kong:Springer-Verlag Tokyo), pp. 509–518.

11. Scrauf, C., Huber, L., and Visalberghi, E. (2008).Capuchin monkeys learn to use weight to selectthe most effective tool to crack open nuts.Anim. Cogn. 11, 413–422.

12. Aumann, T. (1990). Use of stones byblack-breasted buzzard Hamirostramelanosternon to gain access to eggcontents for food. Emu 90, 141–144.

13. Krutzen, M., Mann, J., Heithaus, M.R.,Connor, R.C., Bejder, L., and Sherwin, W.B.(2005). Cultural transmission of tool use inbottlenose dolphins. Proc. Natl. Acad. Sci. USA102, 8939–8943.

14. Hart, B.L., Hart, L.A., McCoy, M., andSarath, C.R. (2001). Cognitive behavior in Asianelephants: use and modification of branches forfly switching. Anim. Behav. 62, 839–847.

15. Thouless, C.R., Fanshawe, J.H., andBertram, B.C.R. (1989). Egyptian vulturesNeophron percnopterus and Ostrich Struthiocamelus eggs - the origins of stone-throwingbehavior. Ibis 13, 9–15.

16. Chappell, J., and Kacelnik, A. (2002). Toolselectivity in a non-primate, the NewCaledonian crow (Corvus moneduloides). Anim.Cogn. 5, 71–78.

17. Chappell, J., and Kacelnik, A. (2004). Selectionof tool diameter by New Caledonian crowsCorvus moneduloides. Anim. Cogn. 7, 121–127.

18. Weir, A.A.S., Chappell, J., and Kacelnik, A.(2002). Shaping of hooks in New Caledoniancrows. Science 297, 981.

19. Weir, A.A.S., and Kacelnik, A. (2006). A NewCaledonian crow (Corvus moneduloides)creatively re-designs tools by bending orunbending aluminium strips. Anim. Cogn. 9,317–334.

20. Fragaszy, D.M., Izar, P., Visalberghi, E.,Ottoni, E.B., and de Oliveira, M.G. (2004). Wildcapuchin monkeys (Cebus libidinosus) useanvils and stone pounding tools. Am. J.Primatol. 64, 359–366.

Department of Psychology & LanguageResearch Center, Georgia State University,PO Box 5010, Atlanta, GA 30302-5010, USA.E-mail: sbrosnan@gsu.edu

DOI: 10.1016/j.cub.2008.12.001

Figure 1. Tool selection by capuchinmonkeys.

Mansinho, an adult male bearded capuchin,cracks open a palm nut on a sandstone anvil.In this case, he was given a choice betweentwo artificial stones, one heavy and smalland the other light and big, and correctlyselected the smaller and heavier stone as hishammer. (Photo by Elisabetta Visalberghi.)

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Hedgehog Signaling: Is Smoa G Protein-Coupled Receptor?

The Hedgehog signal transducer Smoothened is structurally similar toG protein-coupled receptors. Now there is direct evidence that Smoothenedrelies on heterotrimeric G proteins in order to transduce the Hedgehog signal.

Melanie Philipp and Marc G. Caron

The Hedgehog (Hh) signaling pathwayis one of the most important andevolutionarily conserved pathwaysassociated with embryonicdevelopment, and cancer and isinvolved in the formation andhomeostasis of a multitude of tissuesand organ systems [1]. Smoothened

(Smo) is the transducing molecule ofthe extracellular signal Hh following itsinteraction with the receptor Patched.Topographically, Smo resemblesa seven transmembrane domainprotein with a high degree of similarityto the family of G protein-coupledreceptors.

Seven transmembrane receptors arecalled G protein-coupled receptors

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Current Biology

Kif3a

Patched HedgehogSmoothened

Kinesin family member 3a

HeterotrimericG protein

GRK2/3 β-arrestin 2GRK Arrestin

ACαi

βγAdenylate cyclase Protein kinase APKA

P

Kif3a

Gli

Gli

αi

AC

PKAcAMP

βγGRK

Pβγ

GRKArrestin

A

B

P

Figure 1. Two arms of Smo signal transduction.

(A) Activation of Smo decreases the production of cAMP via inhibitory G proteins. PKA isinhibited and does not phosphorylate Gli. Thus, Gli is stabilized and able to initiate transcrip-tion. (B) Phosphorylation of active Smo by GRK2 prepares the association of Smo withb-arrestin 2. Subsequent interaction between b-arrestin 2 and Kif3A facilitates trafficking ofSmo into primary cilia, possibly in vesicles. In the cilium, Smo signal transduction is initiated.

because they signal via interaction withheterotrimeric G proteins. Binding ofa G protein-coupled receptor ligandinduces a conformational change in thereceptor which leads to nucleotideexchange on the G protein and‘dissociation’ of the a and bg subunits.Both subunits are then capable oftransducing the signal via interactionwith effectors and changing levels ofsecond messengers such as cAMP.Depending on their ability to eitherinhibit or stimulate the generation ofsecond messengers or their effectors,heterotrimeric G proteins aresubdivided into four main classes,namely inhibitory (Gi), stimulatory (Gs),

G proteins which activatePhospholipase C (Gq/11) and the G12/13

family [2]. For more than a decade it hasbeen presumed that Smo, because ofits molecular architecture, shouldconnect to heterotrimeric G proteins.However, the evidence provided so farhas been controversial. A recent paper[3] now presents a seeminglyconvincing piece of evidence for Smoto fit the bill of a true G protein-coupledreceptor.

Ogden et al. [3] used a combinationof cell-based assays and Drosophilagenetics to demonstrate therequirement of inhibitory G proteins forSmo-mediated signal transduction.

When they knock down Gai in cellsoriginating from the Drosophila wingimaginal disc (cl8) they find that in thepresence of Hh the production of cAMPis elevated. Consistent with thisobservation, overexpression ofconstitutively active Gai (Gai Q205L) inflies gives rise to ectopic veins in thewing and to increased Hh target geneexpression, both effects consideredHh gain-of-function phenotypes. Gai

Q205L also overrides the phenotype ofthe SmoA5 strain, a dominant negativeSmo transgenic line. At the same time,flies with a deletion of the Gai gene orGai hypomorphs express loweramounts of the Hh target genedecapentaplegic. When the SmoA5strain is crossed to other flies carryinga hypomorphic allele of the cAMPspecific phosphodiesterase, therebyincreasing intracellular cAMP, theSmoA5 phenotype is augmented. Theauthors conclude that Hh signalingoccurs through Smo coupling to Gi,thereby lowering intracellular cAMP.This causes the inactivation of PKA,the kinase believed to prime Glitranscription factors for degradationand the termination of Hh signaling.

These data shed more light on one ofthe initial steps of the Smo signalingcascade. However, the contention thatSmo relies on the coupling toheterotrimeric G proteins in order totransduce the Hh signal has beendiscussed for quite a while. In 1997,Hammerschmidt and McMahon [4]reported that overexpression ofpertussis toxin, an agent whichuncouples a subunits of inhibitoryG proteins from G protein-coupledreceptor-mediated signaling, disruptsmuscle development in zebrafishembryos. However, fish treated in thisway did not completely resemble a lossof Hh function phenotype [4]. Nor didpertussis toxin or Gai Q205L have aneffect on all aspects of Hh signaling inchicken embryos, as spinal cordpatterning was unperturbed and Gli3processing stayed unchanged. On theother hand, transcription of Hh targetgenes in embryonic fibroblasts ofPatched-1 knockout mice seemedto depend on Gi-mediated signaltransduction [5]. Results fromheterologous cell systems publishedby other groups were just ascontroversial. In an RNAi screen forgenes involved in Hh signaling in thesame Drosophila cell line as used byOgden et al. [3] no participation for anyG protein in Hh signaling was evident

Chromosome Dynamics: The Caseof the Missing Condensin

Condensins are conserved protein complexes that play integral roles inchromosome dynamics during mitosis and meiosis. Caenorhabditis eleganshas been thought to be unusual in that it appeared to lack a typical condensin Icomplex. However, recent biochemical excavating in the nematode hasunearthed the ‘missing’ condensin I complex as well as the worm homologs oflong-lost canonical condensin subunits.

Jason R. Ford and Jill M. Schumacher

The 21st century has been anextraordinarily exciting time forbiology. Vast amounts of genomic

information have been compiled, andunderstanding how the genome isorganized, regulated, and packagedremains an intriguing challenge for thescientific community. A significant

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[6]. GTPgS binding experiments inanother Drosophila cell line, however,clearly demonstrated a cyclopaminereversible coupling of Smo to Gi [7].Similarly, it was found in endothelialcells that activation of Gli-dependenttranscription was mediated via Gi andsubsequently PI3K, but not PKA [8].Taken together, the weight of evidencesuggests that some form of Smo mayindeed signal via G proteins. However,whether it can be unequivocallyobserved may depend on the celltype or tissue, the timing of thedifferentiation state of the cell ororganism as well as a host of otherfactors (including species differences).Some of these inconsistencies raise thequestion as to whether more than onesignaling arm may contribute to variousaspects of Smo signaling (Figure 1).

Interestingly, over the last few years,evidence has accumulated that otherG protein-coupled receptor-interactingproteins may contribute to Smosignaling as well. G protein-coupledreceptor kinases (GRK) and b-arrestinsinteract with receptors as part of thedesensitization machinery toterminate G protein-dependentG protein-coupled receptor signaling[9]. However, we now understandthat GRKs and b-arrestins not onlyserve this role but also act as triggersfor endocytosis of G protein-coupledreceptors and can generateG protein-independent signalingcomplexes such as for engagement ofthe ERK and Akt/GSK3 pathways[9,10]. GRKs and b-arrestins may playsimilar roles for Smo. GRKs as well asb-arrestin 2 have been found tointeract with Smo and facilitate Hhsignaling, both in cells as well as inanimals [11–15]. The underlyingmechanism for this is still the subjectof speculation. One possibility may bethe assembly of a signaling complexconsisting of Smo and b-arrestin 2similar to the arrestin-dependentsignaling for ERK and Akt [9,10].However, the fact that Smo needs totraffic in and out of the plasmamembrane suggests that GRK2 andb-arrestin could facilitate Hh signalingby modulating the membranetrafficking of the Smo complex.

Kovacs et al. [16] have recentlyshown that the interaction ofb-arrestin 2 with Kif3A, a motorprotein of the anterograde transportmachinery in cilia, drives Smo intocilia and enables signaling, thusillustrating another potential point of

contribution of these molecules to Smofunction [16]. For b-arrestin toassociate with a G protein-coupledreceptor, the phosphorylation of thereceptor by a GRK is indispensable.Interestingly, the facts that Gbg, whichis a requisite for full activation of GRK2,is required for Smo phosphorylation byGRK2 in cells and that also in fliesa GRK enhances Hh signaling [13,14]bolsters the case for Smo functioning inmany ways like a G protein-coupledreceptor. While there are still numerousunanswered questions as to howG proteins or G protein-coupledreceptor-interacting proteins maycontribute to Hh/Ptc/Smo signaling, itmay be useful to consider thisadditional perspective in futureinvestigations on the mechanism ofHh signaling.

References1. Ingham, P.W. (2008). Hedgehog signalling.

Curr. Biol. 18, R238–R241.2. Stryer, L., and Bourne, H.R. (1986). G proteins:

a family of signal transducers. Annu. Rev. CellBiol. 2, 391–419.

3. Ogden, S.K., Fei, D.L., Schilling, N.S.,Ahmed, Y.F., Hwa, J., and Robbins, D.J. (2008).G protein Galpha(i) functions immediatelydownstream of Smoothened in Hedgehogsignalling. Nature 456, 967–970.

4. Hammerschmidt, M., and McMahon, A.P.(1998). The effect of pertussis toxin onzebrafish development: a possible role forinhibitory G proteins in hedgehog signaling.Dev. Biol. 194, 166–171.

5. Low, W.C., Wang, C., Pan, Y., Huang, X.Y.,Chen, J.K., and Wang, B. (2008). Thedecoupling of Smoothened from Galphaiproteins has little effect on Gli3 proteinprocessing and Hedgehog-regulated chickneural tube patterning. Dev. Biol. 321, 188–196.

6. Lum, L., Yao, S., Mozer, B., Rovescalli, A., VonKessler, D., Nirenberg, M., and Beachy, P.A.(2003). Identification of Hedgehog pathwaycomponents by RNAi in Drosophila culturedcells. Science 299, 2039–2045.

7. Riobo, N.A., Saucy, B., Dilizio, C., andManning, D.R. (2006). Activation of

heterotrimeric G proteins by Smoothened.Proc. Natl. Acad. Sci. USA 103, 12607–12612.

8. Kanda, S., Mochizuki, Y., Suematsu, T.,Miyata, Y., Nomata, K., and Kanetake, H.(2003). Sonic hedgehog induces capillarymorphogenesis by endothelial cells throughphosphoinositide 3-kinase. J. Biol. Chem. 278,8244–8249.

9. Lefkowitz, R.J., and Shenoy, S.K. (2005).Transduction of receptor signals bybeta-arrestins. Science 308, 512–517.

10. Beaulieu, J.M., Sotnikova, T.D., Marion, S.,Lefkowitz, R.J., Gainetdinov, R.R., andCaron, M.G. (2005). An Akt/beta-arrestin2/PP2A signaling complex mediatesdopaminergic neurotransmission and behavior.Cell 122, 261–273.

11. Chen, W., Ren, X.R., Nelson, C.D., Barak, L.S.,Chen, J.K., Beachy, P.A., de Sauvage, F., andLefkowitz, R.J. (2004). Activity-dependentinternalization of smoothened mediated bybeta-arrestin 2 and GRK2. Science 306,2257–2260.

12. Meloni, A.R., Fralish, G.B., Kelly, P.,Salahpour, A., Chen, J.K., Wechsler-Reya, R.J.,Lefkowitz, R.J., and Caron, M.G. (2006).Smoothened signal transduction is promotedby G protein-coupled receptor kinase 2. Mol.Cell Biol. 26, 7550–7560.

13. Philipp, M., Fralish, G.B., Meloni, A.R.,Chen, W., Macinnes, A., Barak, L.S., andCaron, M.G. (2008). Smoothened signaling invertebrates is facilitated by a G proteinCoupled receptor kinase. Mol. Biol. Cell 19,5478–5489.

14. Molnar, C., Holguin, H., Mayor, F., Jr.,Ruiz-Gomez, A., and de Celis, J.F. (2007). TheG protein-coupled receptor regulatory kinaseGPRK2 participates in Hedgehog signaling inDrosophila. Proc. Natl. Acad. Sci. USA 104,7963–7968.

15. Wilbanks, A.M., Fralish, G.B., Kirby, M.L.,Barak, L.S., Li, Y.X., and Caron, M.G. (2004).Beta-arrestin 2 regulates zebrafishdevelopment through the hedgehog signalingpathway. Science 306, 2264–2267.

16. Kovacs, J.J., Whalen, E.J., Liu, R., Xiao, K.,Kim, J., Chen, M., Wang, J., Chen, W., andLefkowitz, R.J. (2008). Beta-arrestin-mediatedlocalization of smoothened to the primarycilium. Science 320, 1777–1781.

Departments of Cell Biology, Medicine, andNeurobiology, Duke University MedicalCenter, Durham, NC 27710, USA.E-mail: m.caron@cellbio.duke.edu

DOI: 10.1016/j.cub.2008.12.010