infection in migratory birds. Science 309,1206.

2. WHO. (2005). Cumulative number ofconfirmed human cases of AvianInfluenza.http://www.who.int/csr/disease/avian_influenza/table_2005_10_10/en/...16/10/2005.

3. Longini, I.M., Jr., Nizam, A., Xu, S.,Ungchusak, K., Hanshaoworakul, W.,Cummings, D.A., and Halloran, M.E.(2005). Containing pandemic influenza atthe source. Science 309, 1083–1087.

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Zoology Department, Oxford University,Oxford OX1 3PS, UK.

DOI: 10.1016/j.cub.2005.10.063

Current Biology Vol 15 No 22R924

Eye Development: Stable Cell FateDecisions in Insect Colour Vision

The retina provides an example of a fundamental property ofdeveloping cells: cell fate decisions are stable. A recent paper reportsa double negative feedback loop that leads to bistable fate decisions inthe colour-detecting photoreceptors of Drosophila.

Matthew Freeman

There is no place in an animal fora cell with an identity crisis. Aconfused cell is unlikely tofunction properly and may bedangerous if, for example, it startsto proliferate inappropriately. Theconcept that cells need to makestable, all-or-nothing fatedecisions was developed byWaddington in the first half of thelast century [1]. He termed thisprocess ‘canalisation’ andillustrated the idea with artisticdrawings of what he called anepigenetic landscape (Figure 1A).His rather theoretical idea hasproved to be correct andfundamental. It is becomingapparent that a variety ofmechanisms exist to ensure thatdevelopmental decisions arerobust [2–4]. Although moststudies have focussed on the

ability of chromatin to converttransient transcriptional states,triggered by apparently fleetingdevelopmental signals, into long-term cellular memory, theincreasingly detailed knowledgeof signalling mechanisms has ledto a recognition that thesepathways themselves havesometimes evolved into robustnetworks that generate stabledecisions [5].

An example of apparentlysimilar cells making distinct fatedecisions are the colour-detecting photoreceptors of theretina. To see colours, our braincomputes the outputs ofphotoreceptors with differentspectral sensitivities. The fruitflyDrosophila has a random mosaicof colour-detectingphotoreceptors in its retina(Figure 1B) [6] and a recent paper[7] has described a mechanism

Figure 1. Robustness and cell fates in the Drosophila eye.

(A) Waddington’s epigenetic landscape. Cell fates are represented by valleys and, as cells‘roll down the hill of development’, they are increasingly unable to cross the interveningridges, i.e. their fates become robust. From [13]. (B) Fluorescent micrograph of aDrosophila retina showing the stochastic distribution of ‘yellow’ (labeled in green) and‘pale’ (red) R8 photoreceptor cells. Image courtesy of Claude Desplan.

that ensures that these cellsmake a robust choice betweenalternative colour-detecting fates.The Drosophila compound eye isformed from about 800 unit eyes(ommatidia), each with sixmonochromatic outerphotoreceptors surrounding twostacked colour detectingphotoreceptors, known as R7and R8. The R7/R8 pair comes intwo randomly distributed forms:70% are ‘yellow’, with R7expressing the rhodopsin Rh4and R8 expressing rhodopsinRh6; the remaining 30% are‘pale’, with R7 expressing Rh3and R8 expressing Rh5 (‘yellow’and ‘pale’ refer to theirappearance under a microscope)[8,9]. Yellow ommatidia detectlonger wavelengths, into thegreen part of the spectrum, whilethe pale ones detect shorterwavelengths, in the blue and UVrange.

The decision between a yellowor pale fate is initiated when theR7 cell in each ommatidiummakes an apparently stochasticchoice of whether to express Rh3or Rh4. This decision is thencommunicated to the adjacent R8cell, forcing it to comply with the‘golden rule’ that R8 must expressRh5 if partnered with an Rh3-expressing R7, or Rh6 if partneredwith a Rh4-expressing R7 [9](Figure 2A). To investigate furtherthe mechanism underlying retinalmosaicism, Mikeladze-Dvali et al.[7] searched for genes expressedin mosaic patterns and found onethat was restricted to yellow R8s.Intriguingly this was the warts(wts) gene (also known as lats),encoding a cytoplasmicserine/threonine kinase alreadyfamous for its role as a tumoursuppressor that regulates cellgrowth and death [10]. Theirattention was then drawn to

Dispatch R925

another gene, melted (melt)which, they discovered by astroke of pure serendipity,showed genetic interactions withwts, indicating some kind offunctional relationship. Melt is acytoplasmic protein with PH-domains and also has past form,being known for its involvement ininsulin signalling [11]. Intriguingly,Melt was found to be expressed ina reciprocal pattern to Wts — onlyin pale R8 cells [7].

That these genes actually havefunctional importance in R8 fatedetermination was addressedgenetically, and the results weregratifyingly straightforward. Bothgenes were required in the R8cells and when wts function wasreduced, all R8 cells adopted thepale fate. When melt was absent,all R8 cells took on the yellowfate. Conversely, ectopicexpression of wts drove all R8cells to the yellow fate, whileectopic melt led to all R8s beingpale.

So, to recap the story so far,wts and melt have reciprocalexpression patterns and functionsin the R8 mosaic: wts specifiesyellow R8 cells, and melt paleones. What does this have to dowith robustness? The answer liesin their effect on each other’sexpression: they form a classicdouble negative feedback loop —a mechanism recognised togenerate bistable decisions asearly as 1961 by Monod andJacob [12]. wts expressionrepresses melt expression andvice versa. Moreover, each ofthese proteins activates its ownexpression. Therefore, a cell withhigh Wts will not express Meltand, conversely, Melt expressingcells will not express Wts. As Wtsand Melt cause the expression ofrh6 and rh5, respectively, thisforms the heart of a robust switchbetween yellow and pale R8 cells(Figure 2B).

With this general concept inplace, the details emerged fromfurther genetics. By studying theeffects of R8 cells that aresimultaneously mutant for wtsand melt (all cells expressed rh5,none rh6), it became clear thatwts was essential for rh6expression; however, if wts wasremoved from the cell, melt was

Figure 2. Feedback stabilised cell fate choice of colour-sensing ommatidia.

(A) Two classes of ommatidia expressing different classes of opsin proteins are used todiscriminate different colours in Drosophila. ‘Yellow’ ommatidia (left) express opsin Rh4in their R7 cell and opsin Rh6 in their R8 cell; they detect longer wavelengths in the visiblespectrum. ‘Pale’ ommatidia (right) express opsin Rh3 in their R7 cells and opsin Rh5 intheir R8 cells; they detect shorter wavelengths in the UV to blue part of the spectrum.(B) A mechanism for ensuring robust fate decisions by R8. At the heart of the mechanismis a bistable negative feedback loop between Wts and Melt. When Wts ‘wins’, rh6 expres-sion is activated. When Melt ‘wins’, rh6 is not expressed and rh5 is de-repressed. Anunidentified signal from Rh3-expressing R7 cells causes Melt to win in pale ommatidia,thereby coupling the Rh3- and Rh5-expressing fates. Modified from [7].

rh1

rh6

rh4rh4

R7

Yellow Pale

rh1rh1 rh1

rh5

rh3rh3

R8

rh4 rh3

rh5rh6

Melt

wts wts

melt

Unknownsignal

Yellow Pale

Current Biology

rh6 rh5

BA

not needed for rh5 expression.These results imply differentroles for Wts and Melt: Wts isdirectly necessary in yellow R8sfor the transcriptional activationof rh6; however, Melt is neededto repress Wts and therebyderepress rh5 in pale R8s, ratherthan for rh5 activation directly.Finally, by studying mutants inwhich the R7 cell was missing, itcould be inferred that theinstructive signal from R7 biasesthe bistable loop in favour of Meltin pale R8s.

To summarise the network thatleads to a robust decision, R8cells express the mutuallyrepressive proteins, Wts andMelt, which form a bistablefeedback loop. Wts is an activatorof rh6 expression and a repressorof rh5. For reasons that remain tobe determined, the default stateof this feedback loop is for Wts tobe on, Melt off, leading to rh6 on;this makes a yellow R8. If,however, an R8 cell receives asignal from an Rh3-expressing R7cell, the repressive loop is biasedin favour of Melt, either byactivating Melt or repressing Wts;the consequent stable repressionof Wts prevents rh6 expressionand depresses rh5.

Of course many questionsremain: what is the elusive signalfrom R7 to R8? What quantitativeproperties stabilise the negative

feedback loop? Does a similarbistable feedback mechanismunderlie the initial stochastic fatedecision by R7, and how is thatdecision tuned to produce a 70:30ratio of yellow to pale ommatidia?And, is there any significance toWts and Melt both leading ‘doublelives’, with their alter egos beinginvolved in growth control? Or isthis just a case of evolutionaryparsimony — Nature reusing thetoolkit of signalling proteinsavailable? There is also morecomplexity in the system thanillustrated in Figure 2B. NeitherWts nor Melt are transcriptionfactors, but their mutualrepression and the ultimatereadout of the feedbackmechanism is at the level of geneexpression; hence, each arm ofthe feedback loop must actuallycomprise a signalling pathwayleading to the nucleus.Nevertheless, the elegant work ofMikeladze-Dvali et al. [7] adds to agrowing appreciation that built-inrobustness is a fundamentalproperty of many signallingpathways. It is important toremember that this feedbackmechanism does not initiate theyellow/pale decision, that’s doneby the R7s; instead, it appears toensure its fidelity and stability.Cells not only have to make fatedecisions, they also have to stickto them.

Current Biology Vol 15 No 22R926

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Tiffany M. Knight and Jonathan M. Chase

The volcanic eruption of Mount St.Helens in 1980 devastated humanlife and property, as well as plantand animal life across an area of 60km2. This catastrophic disturbancehas been intensively studied forthe past 25 years by ecologists,who have gained valuable insightson the successional dynamics thatlead to the rehabilitation of

Ecological SuccesAsh

A new study of plants recolonising thHelens erupted in 1980 is providing iinteractions with herbivores that detecological succession.

Figure 1. The role of herbivores in ecologica

(A) Landscape view of Lupinus lepidus (planbackground. (B) Close-up view of L. lepidusW. Fagan.)

photoreceptor cells observed in vivo.Science 213, 1264–1267.

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terrestrial ecosystems [1].Nitrogen-fixing plants, such aslupines (Lupinus sp.), are critical toprimary succession, as thesespecies enrich the otherwiseintolerable soil and allow otherspecies to subsequently establish[2]. Thus, it is of critical interest tounderstand the factors that controlthe colonization of nitrogen-fixingplants in a successional series.

Although herbivores are knownoften to have important effects on

sion: Out of the

e land devasted when Mount St.mportant new insights into theermine the pattern and outcome of

l succession around a live volcano.

ts with purple flowers) near the blast ridge of killed by stem-boring insects flanked by hea

cycle regulation and tumorigenesis.Biochim. Biophys. Acta 1424, M9–M16.

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13. Waddington, C.H. (1957) The Strategy OfThe Genes. George Allen and Unwin,London.

MRC Laboratory of Molecular Biology,Hills Road, Cambridge CB2 2QH, UK.E-mail: MF1@mrc-lmb.cam.ac.uk

DOI: 10.1016/j.cub.2005.10.062

plant population dynamics [3],both classical [4] andcontemporary [5] views ofsuccession rarely considerherbivores as playing a major rolein successional pathways interrestrial ecosystems. A series ofstudies on the interactionsbetween herbivores and importantnitrogen-fixing plants on MountSt. Helens has been dispelling theview that herbivores play apassive, rather than active, role inthe processes of succession(Figure 1A). Bill Fagan, JohnBishop and their colleagues [6–8]have discovered that lupine-specific lepidopterans depressthe colonization and spread of thenitrogen-fixing lupine, Lupinuslepidus. Of particular importanceare caterpillars of moths in thegenus Filatima, which consume

Mount St. Helens with Mount Adams in thelthy plants. (Both photographs courtesy of