Centrosomes: CNN's Broadcast Reaches the Cleavage Furrow

about the physiology and behaviourof the great apes, excluding thebonobo (or ‘‘pygmy chimpanzee’’,Pan paniscus), which was not thenaccepted as a separate taxon.Quoting Grant (1828), Yerkes andYerkes described the responsesto tickle of an orang-utan ‘‘. . . theorang-outang [is] capable of a kindof laugh when pleasantly excited. Forinstance, if tickled . . . the diaphragm isthrown into action, and reiteratedgrunting sounds, somewhat analogousto laughter, emitted by the animal’’([19], p. 159]). Yerkes and Yerkessummarized numerous observations ofapparent laughter in gorillas, forexample, ‘‘When tickled under the arms

or on the bottom of the foot, [Dinah]chuckles audibly, in a manner closelyverging on a real laugh’’ ([20], p. 1103).

Since the middle of the 19th

century, therefore, researchers havecommented upon the apparentsimilarities and differences in howgreat apes and humans vocally expressjoy. Yerkes stated in 1927: ‘‘It is oftensaid that only man laughs. I am by nomeans certain that this is true. IndeedI am sure it is not unless one defineslaughter subjectively’’ (quoted in [19],p. 470). In their paper in CurrentBiology, Davila Ross et al. [6] havesignificantly advanced this area ofstudy. Firstly, they used the same kindof eliciting stimulus, tickling, to elicitcalls. Secondly, they have comparedjuveniles with juveniles, thus elicitingcalls from apes and humans in broadlysimilar stages of life. Thirdly, theyhave used familiar caregivers to elicitthe tickling, controlling for possible‘stranger effects’. Finally, and perhapsmost importantly, they have analyzedthese joyous emissions in anunprecedented breadth of species,including representatives of everyliving species of great ape. In answer tothe question, ‘‘if we tickle them, do theynot laugh?’’ Davila Ross et al. [6]answer, resoundingly, ‘‘Yes!’’

References1. Goodall, J. (1986). The Chimpanzees of Gombe:

Patterns of Behavior (Cambridge,Massachusetts: Belknap Press).

2. van Hooff, J.A.R.A.M., and Preuschoft, S.(2003). Laughter and smiling: The intertwiningof nature and culture. In Animal SocialComplexity: Intelligence, Culture, andIndividualized Societies, F.B.M. de Waal andP.L. Tyack, eds. (Cambridge, Mass.: HarvardUniversity Press), pp. 260–287.

3. Vettin, J., and Todt, D. (2005). Humanlaughter, social play, and play vocalizationsof non-human primates: an evolutionaryapproach. Behaviour 142, 217–240.

4. Panksepp, J., and Burgdorff, J. (2003).‘‘Laughing’’ rats and the evolutionary

antecedents of human joy? Physiol.Behav. 79, 533–547.

5. Seldon, S.T. (2004). Tickle. J. Am. Acad.Dermat. 50, 93–97.

6. Davila Ross, M., Owren, M.J., andZimmerman, E. (2009). Reconstructing theevolution of laughter. Curr. Biol. 19, 1106–1111.

7. Provine, R.R. (2004). Laughing, tickling, andthe evolution of speech and self. Curr. Dir.Psych. Sci. 13, 215–218.

8. Huxley, T.H. (1863). Evidence as to Man’sPlace in Nature (London: Williams andNorwood).

9. Tinbergen, N. (1959). Behaviour, systematics,and natural selection. Ibis 101, 318–330.

10. Zimmermann, E. (1990). Differentiation ofvocalizations in bushbabies (Galaginae,Prosimiae, Primates) and the significance forassessing phylogenetic relationships. Zeit. furZool. Syst. und Evol. 28, 217–239.

11. Davila Ross, M., and Geissmann, T. (2007).Call diversity of wild male orangutans: Aphylogenetic approach. Am. J. Primatol. 69,305–324.

12. Darwin, C. (1965/1872). The Expression of theEmotions in Man and Animals (Chicago: TheUniversity of Chicago Press).

13. Andrew, R.J. (1962). The origin and evolutionof the calls and facial expressions of theprimates. Behaviour 20, 1–109.

14. Kohler, W. (1973/1925). The Mentality of Apes(Toronto: Liveright).

15. Ladygina-Kohts, N.N. (2002/1935). InfantChimpanzee and Human Child (Oxford: OxfordUniversity Press).

16. Ladygina-Kohts, N.N. (1935). [InfantChimpanzee and Human Child] (in Russian).Full Cyrillic text available on the World WideWeb at http://www.kohts.ru/ladygina-kohts/ichc/html/index.html.

17. Kellogg, W.N., and Kellogg, L.A. (1933). TheApe and the Child: A Study of EarlyEnvironmental Influence upon Early Behavior(New York: McGraw-Hill).

18. Historical Archives of the Department ofPsychology, Florida State University (2002).The Ape and the Child: http://www.psy.fsu.edu/history/wnk/ape.html.

19. Yerkes, R.M., and Yerkes, A.W. (1929). TheGreat Apes: A Study of Anthropoid Life (NewHaven, CT: Yale University Press).

20. Garner, R.L. (1914). Gorillas in their own jungle.Bull. N.Y. Zool. Soc. 17, 1102–1104.

Department of Psychology, School of LifeSciences, University of Sussex, Falmer,East Sussex BN1 9QH, UK.E-mail: davidl@sussex.ac.uk

DOI: 10.1016/j.cub.2009.05.007

Figure 2. Laughing babies.

(A) Infant Donald laughs in response to tick-ling. (B) Infant Gua laughs in response to tick-ling. Photographs from [17].

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Centrosomes: CNN’s BroadcastReaches the Cleavage Furrow

Centrosomin (CNN), a core Drosophila centrosome protein, interacts with thenewly identified protein Centrocortin to promote cleavage furrow formationin the early embryo. Significantly, this activity is distinct from CNN’swell-established role in centrosome-based microtubule organization.

William Sullivan

Centrosome-based astral microtubulearrays play a key role in the formation

and positioning of the cleavage furrow.The work presented in a recent issue ofCurrent Biology by Kao and Megraw [1]identify a centrosome-associated

protein, Centrocortin (CEN), that doesnot influence microtubule organizationbut has a profound effect on furrowformation. These studies have theirconceptual origin in an ingeniousexperiment conducted almost a halfcentury ago [2]. By passing a glass rodthrough a single-celled sand dollarembryo and allowing it to go througha round of division, Rappaport createda syncytial embryo containing twonuclei. When these nuclei divide,furrows form in the expected positionbetween separated sister

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Astralmicrotubules

Rappaportfurrows

Current Biology

Figure 1. Rappaport and metaphase furrows.

Experimentally induced Rappaport furrows (A) and naturally occurring Drosophila metaphase furrows (B) both form between the centrosomesof neighboring sister nuclei. The furrows are centered between opposing astral microtubule arrays, which are required for their formation.Microtubules and actin networks are colored red and blue, respectively.

chromosomes. In addition, a third,ectopic furrow is formed betweenneighboring non-sister centrosomes.Significantly, the region of thecytoplasm in which these ectopicfurrows formed did not containchromosomes or a spindle. Follow-upexperiments demonstrated thata minimal distance between the twocentrosomes and between thecentrosomes and cortex were criticalfactors in inducing formation of thesefurrows [3]. Equivalent experimentsperformed in mammalian cells as wellas in other systems demonstrated thisto be a general phenomenon [4].

One explanation for the origin ofthese ectopic furrows, now referred toas Rappaport furrows (Figure 1A), isthat activities associated with thecentrosomes and their associatedastral microtubules are sufficient forinduction of the cleavage furrow [5].Rappaport’s experiments were key tothe development of the equatorialstimulation model of cytokinesis. Thismodel proposes that positive signalsfrom opposing, overlapping astralmicrotubules interacting with thecortex at the cell equator provide theinitial signals inducing cleavage furrowformation [6]. While it is now clear thatadditional features of the mitoticspindle, such as the central spindle,also play critical roles in furrowinduction and position, recent studieshave provided molecular support forthe equatorial stimulation model [7,8].Bringmann and colleagues [9] haveidentified cortically localized LET-99and the interacting heterotrimericG-proteins GOA-1 and GPA-16 asessential for astral-microtubule-induced furrow formation in

Caenorhabditis elegans embryos.Mechanical displacement of thespindle resulted in an equivalentdisplacement of LET-99 such that italways concentrated at the spindlemidpoint and the presumptive site offurrow formation. Although the exactmechanism by which LET-99 ispositioned is unknown, the authorssuggest LET-99 responds tomicrotubule-induced cortical tension.

Thus, centrosomes play a key role incytokinesis through the generation ofastral microtubule arrays that interactwith the cortex to induce furrowformation. As reported in their recentpaper, Kao and Megraw [1] tackle theless well explored, but equallyimportant, issue of whethercentrosome-associated activities,distinct from organizing microtubules,are required for cleavage furrowformation. These studies takeadvantage of the unique furrows thatform during the initial divisions ofDrosophila embryogenesis. Followingfertilization and nine rounds of rapidsynchronous divisions in the interiorof the embryo, syncytial nuclei areorganized in a monolayer along theactin-rich embryo cortex [10]. Duringinterphase of these cortical divisions,each nucleus and its apicallyassociated centrosome pair organizeactin into caps encompassing thecentrosomes and their asters. As thenuclei progress into prophase withseparated centrosomes, the actinreorganizes into furrows thatencompass each maturing spindle(Figure 1B). Although the timingand positioning of these furrows isunusual, they are structurally andcompositionally indistinguishable from

conventional cytokinesis furrows. Inthe absence of these furrows, knownas pseudocleavage or metaphasefurrows, neighboring spindles fuse [11].Thus, metaphase furrows function asbarriers between the highly dynamic,closely packed syncytial spindles.During the late cortical divisions,thousands of metaphase furrows forminterlocking rings across the entireembryo cortex. With respect to furrowposition, these naturally occurringmetaphase furrows are equivalent tothe experimentally induced Rappaportfurrows [12]. Like Rappaport furrows,metaphase furrows form betweenneighboring non-sister centrosomes inthe absence of chromosomes andspindles. It appears that their positionis determined by overlapping astralmicrotubule arrays during earlyprophase.

Kao and Megraw [1] began theirstudies by characterizinga hypomorphic cnn allele, cnnB4.Drosophila Centrosomin (CNN) isa core centrosomal protein required fornormal pericentriolar materialorganization and astral microtubuleassembly [13,14]. In contrast to nullalleles, cnnB4 had no discernable effecton microtubule organization yet stillproduced severe disruptions in furrowformation. Thus, the microtubule- andfurrow-organizing functions of CNN aregenetically separable. Sequenceanalysis revealed a point mutation inthe conserved carboxy-terminaldomain of CNN. Reasoning thatproteins interacting with this domainwould be essential for CNN’s role infurrow formation, Kao and Megraw [1]identified CEN through two-hybridanalysis. CEN has uncharacterized

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mammalian orthologs, including thehuman genes cerebellar degenerationrelated-2 (Cdr2) and Cdr2-like [15].CEN localization partially overlapsCNN at the centrosome. During theinterphase/prophase transition, CENlocalizes between centrosome pairs.Upon centrosome separation, as thenuclei enter prophase, CEN segregatesasymmetrically with only one of the twocentrosomes. As no other asymmetrieshave been identified during thesedivisions, this was unexpected. Thefunctional significance of thisasymmetric localization remainsunclear. Significantly, CEN alsolocalizes to the metaphase furrows.These localization studies combinedwith the fact that CEN specifically bindsthe carboxy-terminal domain of CNNmake it an excellent candidate fora molecular link between thecentrosomes and cleavage furrow.

Analysis of cen mutants support thisinterpretation. Strong cen allelesproduce phenotypes very similar to thecnnB4 hypomorph described above.Like the cnnB4 mutant, cen mutants hadno effect on microtubule organization.In addition, interphase actin-caporganization was normal in thesemutants. However, cen mutantembryos displayed a high frequencyof broken and weak furrows duringprophase and metaphase. Thesedefects readily account for thenumerous spindle fusions observed incen mutant embryos. Taken together,these data support a model in whichthe conserved carboxy-terminaldomain of centrosome-localized CNNis essential for proper cleavage furrowassembly. CNN signaling to the furrow

Learning and MemoBehaviors Become

A recent study of how food-seeking behcompulsive provides new insights into tconditioning.

Gyorgy Kemenes

Smokers, drinkers and drug addictsfind it difficult to kick their respectivehabit not only because they aredependent on the substances theytake, but also because they often

relies on CEN, a protein that localizes atthe centrosome and cleavage furrow.

The specific function of CEN at thecentrosomes and furrows remainsunclear. Previous studiesdemonstrated that proper organizationof the centrosome-associatedrecycling endosome is required forvesicle-based membrane delivery andproper actin organization at themetaphase furrows [16,17]. Mutantsthat disrupt recycling endosomeorganization produce furrow defectsstrikingly similar to the cen mutantphenotypes [16]. However, cenmutations do not appear to disruptrecycling endosome organization.Thus, in addition to astral microtubuleformation and recycling endosomeorganization, Kao and Megraw [1] haveidentified a new centrosome-associated activity required for furrowformation. Fortunately, theidentification of CEN provides a meansto characterize the components andfunction of this unexpected signalingpathway between the centrosome andcleavage furrow.

References1. Kao, L.R., and Megraw, T.L. (2009).

Centrocortin cooperates with Centrosominto organize drosophila embryonic cleavagefurrows. Curr. Biol. 19, 937–942.

2. Rappaport, R. (1961). Experiments concerningthe cleavage stimulus in sand dollar eggs.J. Exp. Zool. 148, 81–89.

3. Rappaport, R. (1986). Establishment of themechanism of cytokinesis in animal cells. Int.Rev. Cytol. 105, 245–281.

4. Rieder, C.L., Khodjakov, A., Paliulis, L.V.,Fortier, T.M., Cole, R.W., and Sluder, G. (1997).Mitosis in vertebrate somatic cells with twospindles: implications for the metaphase/anaphase transition checkpoint and cleavage.Proc. Natl. Acad. Sci. USA 94, 5107–5112.

5. Oegema, K., and Mitchison, T.J. (1997).Rappaport rules: cleavage furrow induction in

ry: How Sea SlugCompulsive

avior in the sea slug Aplysia becomeshe neural mechanisms of operant

acquire various forms of habitual oreven compulsive behavior as partof their addiction [1]. Behaviorsassociated with natural rewards, suchas food or sex, can also becomecompulsive. At the systems level,a great deal is known about the

animal cells. Proc. Natl. Acad. Sci. USA 94,4817–4820.

6. Burgess, D.R., and Chang, F. (2005). Siteselection for the cleavage furrow at cytokinesis.Trends Cell Biol. 15, 156–162.

7. Bringmann, H., and Hyman, A.A. (2005). Acytokinesis furrow is positioned by twoconsecutive signals. Nature 436, 731–734.

8. McCollum, D. (2004). Cytokinesis: the centralspindle takes center stage. Curr. Biol. 14,R953–R955.

9. Bringmann, H., Cowan, C.R., Kong, J., andHyman, A.A. (2007). LET-99, GOA-1/GPA-16,and GPR-1/2 are required for aster-positionedcytokinesis. Curr. Biol. 17, 185–191.

10. Mazumdar, A., and Mazumdar, M. (2002). Howone becomes many: blastoderm cellularizationin Drosophila melanogaster. Bioessays 24,1012–1022.

11. Sullivan, W., Minden, J.S., and Alberts, B.M.(1990). daughterless-abo-like, a Drosophilamaternal-effect mutation that exhibits abnormalcentrosome separation during the lateblastoderm divisions. Development 110,311–323.

12. Sisson, J.C., Rothwell, W.F., and Sullivan, W.(1999). Cytokinesis: lessons from rappaportand the Drosophila blastoderm embryo. CellBiol. Int. 23, 871–876.

13. Li, K., and Kaufman, T.C. (1996). The homeotictarget gene centrosomin encodes an essentialcentrosomal component. Cell 85, 585–596.

14. Megraw, T.L., Li, K., Kao, L.R., andKaufman, T.C. (1999). The centrosomin proteinis required for centrosome assembly andfunction during cleavage in Drosophila.Development 126, 2829–2839.

15. Sutton, I. (2002). Paraneoplastic neurologicalsyndromes. Curr. Opin. Neurol. 15, 685–690.

16. Riggs, B., Fasulo, B., Royou, A., Mische, S.,Cao, J., Hays, T.S., and Sullivan, W. (2007). Theconcentration of Nuf, a Rab11 effector, at themicrotubule-organizing center is cell cycleregulated, dynein-dependent, and coincideswith furrow formation. Mol. Biol. Cell 18,3313–3322.

17. Cao, J., Albertson, R., Riggs, B., Field, C.M.,and Sullivan, W. (2008). Nuf, a Rab11 effector,maintains cytokinetic furrow integrity bypromoting local actin polymerization. J. CellBiol. 182, 301–313.

Department of Molecular, Cell andDevelopmental Biology, University ofCalifornia, Santa Cruz, CA 95066, USA.E-mail: sullivan@biology.ucsc.edu

DOI: 10.1016/j.cub.2009.05.012

neural mechanisms underlying theformation of some types of compulsivebehavior, for example compulsivefood-seeking [2]. But we still know littleabout the learning-induced cellularmechanisms that underly the switchfrom sporadic spontaneous actionsto compulsive behavioral acts. Ina study published recently in CurrentBiology, Nargeot et al. [3] used themarine mollusc Aplysia to revealnovel cellular and networkmechanisms that contribute to theacquisition of compulsivefood-seeking behavior throughoperant conditioning.