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2. Sinervo, B. (1999). Mechanistic analysis ofnatural selection and a refinement of Lack’sand Williams’ principles. Am. Nat. 154(suppl.),S26–S42.

3. Bennett, P.M., and Owens, I.P.F. (2002).Evolutionary Ecology of Birds: Life Histories,Mating Systems and Extinction (Oxford: OxfordUniversity Press).

4. Creighton, J.C., Heflin, N.D., and Belk, M.C.(2009). Cost of reproduction, resource quality,

and terminal investment in a burying beetle. Am.Nat. 174, 673–684.

5. Lock, J.E., Smiseth, P.T., and Moore, A.J. (2004).Selection, inheritance, and the evolution ofparent-offspring interactions. Am. Nat. 164,13–24.

6. Lock, J.E., Smiseth, P.T., Moore, P.J., andMoore, A.J. (2007). Coadaptation of prenatal andpostnatal maternal effects. Am. Nat. 170,709–718.

Haltere

Compound eye Muscular neck

Visual targetMot

Visuahea

Stable gazeA B

Figure 1. Head movements that stabilize the dsystems.

(A) A visual target such as another fly is fixatedarticulated head is moved by muscles that recefrom gyroscopic sense organs called halteres.the neck muscles to turn the head and stabilizeby the halteres and results in coaxial contra-rot

Evolution & Ecology Research Centre, Schoolof Biological, Earth and EnvironmentalSciences, University of New South Wales,Sydney, New South Wales 2052, Australia.E-mail: rob.brooks@unsw.edu.au

DOI: 10.1016/j.cub.2009.10.065

Neurobiology: Fly Gyro-Vision

Flies stay on course using a combination of high performance vision anda specialized sensory gyroscope. A new study reveals that these disparatemodalities are wired together.

ion

lly evokedd rotation

Haltere evokedhead counter-rotation

Wind

C

Current Biology

irection of gaze are evoked by two sensory

on the forward-looking compound eye. Theive input from the compound eyes and also(B) Movement of the visual target activates

gaze. (C) A wind gust on the body is detectedation of the head to stabilize gaze.

Mark A. Frye

So you think you can see? Humanretinal ganglion cells are roughlypredicted to transmit visualinformation at the equivalent of 10 bitsper second [1], which is likely anunderestimate of photoreceptorcapacity. Foveal photoreceptorsmay transmit up to 100 bits persecond in full daylight, but thisperformance nevertheless pales incomparison to the 1000 bits persecond transmitted by thephotoreceptors of a flesh fly [2].Put another way, the 16 Hz flickerfusion cut-off for human conesin part enables us to be fooled intoperceiving smooth motion in moviesdisplayed at 30 frames per second.Yet flies perceive image frequencieswell in excess of 100 Hz, and wouldtherefore see our movie as somethingakin to a slide show.

Though fly visual transduction is thefastest yet measured in any animal, theextreme retinal image speeds achievedduring routine flight maneuvers [3]are well beyond those which canbe effectively compensated byvisuo-motor reflexes [4]. Therefore, likehumans, flies reduce the corruptinginfluence of image blur duringlocomotion by actively moving theirheads to stabilize their gaze [5]. Justlike a ballet dancer in a pirouette fixeshis gaze on one spot to maintainstability, a fly steering its body intoa turn contra-rotates its head to keepthe visual world reasonably still [6].A new study [7] shows that the extremevisual capabilities of flies are due in partto the convergence of multiple sensorymodalities upon the control of headposture for stable gaze.

Maintaining stable gaze whilechasing down a visual target, such asa territorial invader or potential mate,requires adjusting head posture tofixate the visual world and also tocounteract movements of the body.Visual inputs from the compound eyesare segregated into parallel processingpathways specialized to encodepatterns of panoramic optic flowgenerated during self motion [8,9],or small moving targets generatedby prey or conspecifics [10]. Bodydynamics are encoded by gyroscopicsensory organs called halteres thatbeat back and forth like the wingsand during body rotation generateout of plane reaction forces that aredetected by mechanoreceptors at theirbase [11].

Visual and mechanosensory signalsconverge on the neck musculoskeletal

system to pivot the head [7]. Thus,if a visual target drifts laterally(Figure 1A), visual activation of theneck motor system producesa compensatory head turn (Figure 1B).Similarly, mechanical deflection of thebody and haltere sensors by a gustof wind evokes a contra-rotatingcompensatory head movement(Figure 1C). It would thus appearthat the visual and mechanosensorysystems are well synchronized forthe task of stabilizing gaze.

‘‘Ay, there’s the rub’’: haltere sensoryneurons respond to stimulation withinmicroseconds [12], and in turn mediatechanges in head postural positionwithin three milliseconds of a sensorydisturbance [13]. This behaviorallatency is ten times shorter than theactivation delay within visual motionprocessing neurons [14]. The timediscrepancy is evident within the veryearliest stages of sensory transduction.In contrast to the rapid direct activationof ion channels in mechanoreceptors,photoreceptor signaling in flies usesa comparatively sluggish G-proteinsignaling cascade. Add to that the

Haltere

Compound eye∫ dt

Neck muscle “actuator”Integrate

and fire model

Current Biology

Figure 2. Model for multisensory control ofgaze.

Subthreshold visual signals from the com-pound eye and the mechanosensory signalsfrom the halteres are integrated to bring theneck steering muscle (represented by ahydraulic actuator) to firing threshold. Eithermodality alone is insufficient to achieve thethreshold level needed for actuation.

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numerous computations required forvision and in the end, fast as it may be,the fly visual system cannot keep pacewith the temporal performance of thehaltere sensory system, not by a longshot.

The kinetics of the two sensorysystems are reflected to some extentin the frequency tuning of visual andhaltere mediated flight reflexes; visualstabilization behaviors peak for slowstimuli, whereas mechanosensoryequilibrium behaviors increasemonotonically with the rate ofstimulation [15]. Therefore, at bothcellular and behavioral levels, theoutput signals from the two sensorypathways operate on very differenttime scales. How are the two resolvedfor gaze stabilization?

To address this question, Huston andKrapp [7] devised a method to recordthe intracellular membrane potentialof neck motor neurons while visuallystimulating the compound eyes andmechanically stimulating the halteres.The visual stimuli were projected froma standard television-like display.Stimulating the halteres of animmobilized animal required moreingenuity; the solution was to gluea metal particle onto the haltere andoscillate the appendage in a cyclingmagnetic field. Thus, the neck motorneuron could be excited by visual input,mechanosensory input, or bothsimultaneously.

Huston and Krapp [7] found thatsome of the neck motor neurons wereexcited by visual stimuli alone, thuscorroborating previous findingssuggesting that this group of muscles is

directly excited by optic flow-sensitiveinterneurons in the brain [16]. However,another group of neck motor neuronsshowed visual excitation only whenco-activated with haltere sensory input.Neither visual nor mechanosensorystimuli alone elicited action potentials.Only when the haltere was beingoscillated did concomitant visualstimuli result in robust directionallyselective spiking responses.

The general finding that visual andmechanosensory stimuli both activatethe neck motor system [7] wassomewhat expected because it hadbeen established that each sensorymodality evokes head movements(Figure 1). The ‘‘eureka’’ came from thespecific way that the different sensorycues were fused. Haltere input excitesthe neck motor circuit with each halterebeat, but the membrane excitationis below the threshold required to firean action potential. Visual excitationalone is also subthreshold, but thetwo converging signals are temporallyintegrated to bring the motor neuronto firing threshold, activate the muscle,and turn the head (Figure 2).

The specific advantage here is thatthe relatively slow tonic visual signalsare effectively gated by the fastwingbeat-synchronousmechanosensory signals. In this waythe neck muscle system is triggeredin temporal register with the beatinghalteres. That is to say the haltere input‘clocks’ the visual input. Therefore,one input channel (haltere) effectivelytransforms the other input channel(compound eye) into a fast behaviorallyrelevant motor code. The disparatetime scales are effectively resolved.

The fusion of inputs from thecompound eyes and halteres helpsto explain why flies only turn theirheads to track visual motion whenthe halteres are beating - during flightor walking [13,17]. But what is theadvantage of this complicatedmultimodal convergence? The answerlies within the organization of relatedsensory-motor transformations.

It turns out that haltere sensorysignals have the same generalinfluence over wing steeringmuscles that they have over neckmuscles — synchronous excitatoryintegration toward firing threshold [18].A gust of wind that twists the bodyin flight would therefore excite thehalteres and evoke a rapid correctiveresponse in wing kinematics.Additionally, it would also seem

obvious that in order to respond tovisual movement, visual signals shouldactivate the wing muscles. Strangelyenough there is no evidence directlylinking visual signals to the wing motorsystem. Instead, visual signals projectdirectly to the haltere muscles ina manner very similar to the neck motorsystem [19].

We find in flies several multisensoryreflex arcs in which visual signalscontrol the halteres, the halterescontrol the wings, and both visualand haltere signals control the neckto move the eyes in turn modifyingthe incoming visual signals. It standsto reason that stabilizing the directionof gaze is critically important to theoverall flight control effort, becauseinformation capacity is irretrievablydegraded when the speed of optic flowexceeds the encoding capacity ofmotion processing pathways.

It therefore seems to be highlyadvantageous that fastmechanosensory feedback effectivelyintercedes in the control of head andwing kinematics. When these resultsare considered alongside an emergingliterature on cross-modal visual,olfactory, and antennalmechanosensory mediated behaviorin flies [20], the emerging multimodalcontrol systems appear to provide botha mechanistic basis for the extremesensory-motor performance of fliesin particular, and also a generalconceptual framework for howhigh-level computational behavioremerges from low-level circuitinteractions and algorithms.

References1. Koch, K., McLean, J., Segev, R., Freed, M.A.,

Berry, M.J., II, Balasubramanian, V., andSterling, P. (2006). How much the eye tells thebrain. Curr. Biol. 16, 1428–1434.

2. Niven, J.E., Anderson, J.C., and Laughlin, S.B.(2007). Fly photoreceptors demonstrateenergy-information trade-offs in neural coding.PLoS Biol. 5, 828–840.

3. Wagner, H. (1986). Flight performance andvisual control of flight of the free-flying housefly(Musca domestica L.) III. Interactions betweenangular movement induced by wide- and smallfield stimuli. Phil. Trans. Roy. Soc. B 312,581–595.

4. Duistermars, B.J., Chow, D.M., Condro, M., andFrye, M.A. (2007). The spatial, temporal, andcontrast properties of expansion and rotatationflight optomotor responses in Drosophila.J. Exp. Biol. 210, 3218–3227.

5. Hengstenberg, R. (1988). Mechanosensorycontrol of compensatory head roll during flightin the blowfly Calliphora erythrocephala.J. Comp. Physiol. A 163, 151–165.

6. Schilstra, C., and van Hateren, J.H. (1998).Stabilizing gaze in flying blowflies. Nature 395,654.

7. Huston, S.J., and Krapp, H.G. (2009). Nonlinearintegration of visual and haltere inputs in fly

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neck motor neurons. J. Neurosci. 29,13097–13105.

8. Kern, R., van Hateren, J.H., Michaelis, C.,Lindemann, J.P., and Egelhaaf, M. (2005).Function of a fly motion-sensitive neuronmatches eye movements during free flight.PLoS Biol. 3, 1130–1138.

9. Krapp, H.G., and Hengstenberg, R. (1996).Estimation of self-motion by optic flowprocessing in single visual interneurons. Nature384, 463–466.

10. Nordstrom, K., Barnett, P.D., and O’Carroll, D.C.(2006). Insect detection of small targets movingin visual clutter. PLoS Biol. 4, 378–386.

11. Frye, M.A. (2007). Behavioral neurobiology:a vibrating gyroscope controls fly steeringmaneuvers. Curr. Biol. 17, 134–136.

12. Fox, J.L., and Daniel, T.L. (2008). A neural basisfor gyroscopic force measurement in thehalteres of Holorusia. J. Comp. Physiol. A 194,887–897.

13. Sandeman, D.C., and Markl, H. (1980). Headmovements in flies (Calliphora) produced bydeflexion of the halters. J. Exp. Biol. 85, 43–60.

14. Warzecha, A.K., and Egelhaaf, M. (2000).Response latency of a motion-sensitive neuronin the fly visual system: dependence onstimulus parameters and physiologicalconditions. Vis. Res. 40, 2973–2983.

15. Sherman, A., and Dickinson, M.H. (2003). Acomparison of visual and haltere-mediatedequilibrium reflexes in the fruit fly Drosophilamelanogaster. J. Exp. Biol. 206, 295–302.

16. Huston, S.J., and Krapp, H.G. (2008).Visuomotor transformation in the fly gazestabilization system. PLoS Biol. 6, 1468–1478.

17. Hengstenberg, R. (1991). Gaze control inthe blowfly Calliphora: a multisensory,two-stage integration process. Semin.Neurosci. 3, 19–29.

18. Fayyazuddin, A., and Dickinson, M.H. (1996).Haltere afferents provide direct,

electrotonic input to a steering motor neuronin the blowfly, Calliphora. J. Neurosci. 16,5225–5232.

19. Chan, W.P., Prete, F., and Dickinson, M.H.(1998). Visual input to the efferent controlsystem of a fly’s ‘‘gyroscope’’. Science 280,289–292.

20. Duistermars, B.J., Chow, D.M., and Frye, M.A.(2009). Flies require bilateral sensory input totrack odor gradients in flight. Curr. Biol. 19,1301–1307.

Department of Physiological Science,Howard Hughes Medical Institute, Universityof California, Los Angeles, CA 90095, USA.E-mail: frye@ucla.edu

DOI: 10.1016/j.cub.2009.11.009

Metastasis: Alone or Together?

Recent studies of carcinoma progression reveal the distinct routes ofdissemination of discrete carcinoma cell populations and suggest thatmelanoma cell dissemination is linked to differentiation rather thanstemness status.

Jean Paul Thiery

Classical models of tumor invasion andmetastasis implicate the progressiveaccumulation of genetic and epigeneticalterations in the generation of locallyinvasive and metastatic tumors.Although clonal in origin, malignantcells rapidly become heterogeneousand coexist with a variable amount ofstroma in the tumor. The originaldogma was that a small subset ofclones becomes susceptible toprogress and acquire a metastaticpotential [1]. It was later shown thatsimilar clusters of gene expressionprofiles can be found at differentstages of tumorigenesis, suggestingthat the metastatic potential wasacquired at an early stage by thewhole tumor rather than by a subsetof malignant cells [2]. More recentstudies have revealed that somemalignant cells in the primary tumoractivate, in part, a complex signalingprogram to colonize specificorgans and subsequently formmacrometastases [3]. None of thesestudies, however, has thoroughlyanalyzed cell behavior in a primarytumor mass during its expansion.

New imaging techniques havecaptured the behavior of endothelialcells in situ during tumor angiogenesis[4], as well as the behavior of otherstromal and malignant cells [5].

Intravital imaging, using multiphotonmicroscopy, considerably reducesfluorophor bleaching and theproduction of oxygen radicals andallows for the visualization of differentcell behaviors. At the same time,increasing the optical resolution viasecond harmonic generation allowsfor the detection of extracellularmatrix (ECM) fibers containinghelical proteins, such as collagen.With these techniques, studies havedemonstrated that some carcinomacells have a much higher speed oflocomotion in vivo than in 2D or 3Din vitro motility. Also, continuousmonitoring of carcinoma cell migrationwithin the extracellular environmenthas revealed an amoeboid mode ofmovement of solitary cells that looselyinteract with ECM fibers via focalcomplexes and do not induce tensionin cells: carcinoma cells can thereforereach blood vessels and intravasate [5].

Using a similar intravital imagingapproach, new findings from Sahaiand colleagues [6] have revealed thatrat mammary MTLn3 metastaticadenocarcinoma cells, whentransplanted into the fat pad of wild-typemice, migrate either as cell collectivesor as solitary cells. The solitary cells,constituting about 5% of the carcinoma,move much more rapidly (150 mm/h)than the compact cell clusters andintravasate into blood vessels, whereas

cells in clusters preferentially invade theproximal inguinal lymph nodes wherethey remain mostly immobile. Thistransient acquisition of motility wasfound to be driven by transforminggrowth factor b (TGFb) signaling,particularly for the solitary cells,which had undergone an epithelial–mesenchymal transition (EMT) [7].Interestingly, the TGFb signaling effectorSmad2 was localized to the nucleus inthese cells, although this localizationwas transient because metastatic cells,forming large clusters in lymph nodesand in the lung, have a cytoplasmiclocalization of Smad2. The transientnature of TGFb signaling was confirmedwith a TGFb-dependent reporter gene;however, TGFb signaling was found tobe active in some non-migratory cells,suggesting that TGFb signaling may benecessary but not sufficient to inducemotility. In vitro studies confirmed thatTGFb can induce EMT in carcinomacells, whereas epidermal growth factor(EGF), not TGFb, triggered collectivecell migration.

TGFb target genes involved in theswitch from collective to single cellmotility were identified, including thesmall GTPases RhoA and RhoC, whichare both important for actomyosincontractility; EMT could only beinhibited when both small GTPaseswere depleted by siRNA. Furthermore,knockdown of the TGFb targets MRIP,Farp-1, c-Jun or the EGF receptor alsoreduced cell scattering. Some TGFb

target genes were implicated in theregulation of adherens junctions,whereas others may be instrumentalin the control of individual celllocomotion, such as Nedd9, whichpromotes actin polymerization, or