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Pens, ‘l’.l). et af. ( 19°2 /. Nc,f~lf]f]l~y.si[~/. 68, S18-527 Payne, B.R. (1994) Belw. Brain Res. 64, 55-64 Sun, .1-S. etal. ( 1994) i “i.f[ml Nefmmi. 11, 189-197 Payne, B.R. ( 1990) L’is{d Ne[mx’i. 4, 445-474 Sandell, J.H. and Schiller, P.H. (1982) J. Newop)ysid. 48, :38-48 Bullicr, J. etal./. Pby.$Jd.Pdri.s(in press) (19S1) Braif] Rc,s.208, 409-415 Geisert, E.E. etal. McClurkin, J.W. and Marrocco, R.T. (1984) /. Pbysiol. 348, 135-152 59 Schmielau, F. and Sir]ger, W. ( 1977) Bruit] R(+. 12[), 354-361

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60 Sillito, A.M. et al. (1994) Natfm 369, 479-482 601-617 61 Mc(;lurkin, J.W. et al. (1994) Visual Nfwmt-i. 11, 62 Villa, A.E.P. (1988) Znflfwmf’dc [’fmr[-e C4r4hruk .sur l’Activit4 Spwtaml, et ~vo@e d[{ Tb[l/[JmIM Amiitif du (Mat, Presses Imprivite 63 Ghosh, S. etd (1994) Exp. Bruir? RC>S. 100, 276-286 64 Yuan, B. et al. (1986) Nefmm’ieffcc 8, 3611-3617 65 Diamond, M. F,. et al. (1992) /. Cotnp. Nef/ro/. :+19, 6(,-84 66 Schiller, P.H. et al. (1974) 1. Ncnropbysid. 37, 181-194 67 C)gasawara, K. et al. ( 1984) 1. Newophy.$id. 52, 1226-1245

Engrailed and retinotectal

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Sylvie Retaux and William A. Harris We examine the role of the Engrailedhomeobox gene in establishment of local tectal topography. In the mesencephalon,a gradient of i%grailedappears early and defines the rostrocaudal axis of the tectum. Various experiments that cause ectopic Engrailed expression cause predictable readjustments of the retinotectal map. The newly discovered‘realisators’ of the retinotopic map, suchas receptor tyrosine kinaseIigandsELF-l and RAGS could be controlled directly by Engrailed. Indeed, recent results show that Engrailedregulatesthe expressionof these ligands.The Engrailed gradient itself appears to be set up by signalsincluding FGF8 and WNT 1,allowing us to begin to trace the molecular cascadethat is responsiblefor the correct wiring of the visual projection back into the early embryo. Trerlci., ,Nwrmc-i. (1996)

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pressionof downstream‘realisator’targetgeneswhich, in some cases, are cell-surfacemolecules and signaling factorsthat givelocal molecularcharacterto the tissues expressingthem. Indeedsomeof the targetsof homeotic genes in both flies and vertebrates are membraneassociated molecules that affect axonal growth and guidanceA-7. Over the past few years, the discoveryof several patterning transcription factors (such as the ones :schematizedin Fig. 1A) expressedspecificallyin the vertebratebrain have been described (for review, see Ref. 8). The expression of these genes in different subregionsof the forebrainand midbrainhas strengthened the hypothesisthat the chordatebrain arisesfrom an ancestralregionalizedstructure91(]. The mosaicof the expressionpattern of these transcriptionfactors covers the brain like a multicolored map of the neural territories, and providesa rich sourceof informationwhich could in principle control the local cues that guide axons,in the brain (Fig. 1A). Intriguingly,it has been noticed that boundariesof homeobox gene expression in the embryonic vertebrate brain often coincide with the tracts of early projection neurons in the brain’‘-’:].In fact, in zebrafish, where the expression pattern of these homeobox genes has been experimentally or genetically altered, the pioneeringtracts of brain follow new routes along the changed boundaries of homeobox gene expression““. Recently, the idea that homeobox genes control local information responsible for axon guidance Biok)
EVELOPINGRFi!’INALGANGLIONCELLS send out axons that l]~vigateover a variety c)fdifferent brain regions to arri~eat their distant specific targets in the optic tectum w thalamic nuclei (Fig. 1A).When they arrive,they obe’. a generalrule of organizationof connectivity based 01 topography.Thus, nasal retinal axons project to cau,ial tectum while temporal axons project to rmtral teclum (Fig. IB). In the orthogonal dimension, dorsal relinal axons project to the lateral tectum while ventral axons project to the medial tectum. That axons foil )Wtheir normal course along the optic tract when th tectal primordium is ablated], and are predictable}deflected when the neuroepithelium of the presu]nptiveoptic tract is rotatedz,suggests that optic axonLabwdofre de retinal axons respond~ngto local cueswithin the target, Newwchifniefindingsthat originallyledRogerSperryto formulatehis Atfatmie, lmtitut theory of chemospe(ificity;. Becauseretinal axons rede.sNwmscienm, spond to local positional information in the neuroBerrlard, 9 epithellum, both on the way to and within their tar75005 Paris, gets, it follows that there are differentiallyexpressed Frame, and molecular-guidancec{leson the surfacesof the cellsover Wi[lia/n A. Harris which the retinal axons grow.A keyquestionis how do is at tbe [kptof theseguidancemolecldesgetexpressedat the rightplace?

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ErzgraiZed was originally discovered as a segment In en mutants, pospolarity gene in DrosophiZa16’7. terior segmental identity is transformed to anterior. For example, en mutant wings are mirror symmetric having two front halves and no back half. Cloning of the en gene showed it to be a homeobox gene expressedin the posterior compartments of segments. When the gene is misexpressedin anterior compartments, it transformsthem into a posteriorcharacter.A monoclinal antibody to a highly similar Drosophila gene product, INVECTED, was found to recognize EN proteins in a number of species including vertebratesls.Vertebratehomologs of the en genewerethen discoveredin frogs, fish, chick and mice. Vertebrates, by and large, have two Engrailedgenes Enl and En2, although fish have three. Enl and Erz2are very early markersof the midbrain-hindbrain boundaryand are turned on at the mid-neural plate stage19-z3. In Enl knockout mice and Enl En2 doubleknockout mice the mesencephalon and cerebellum are simply absent, suggestingthat En is crucial for the development or determination of this brain region24z5.En2 is expressedslightly later than Enl in the mouse and En2 knockouts have little effect on the dorsal midbrain26. When the En2 gene is knocked into the Enl locus, it rescues the Enl phenotype, showing that the two genes are functionally equivalent, and suggestingthat the periodof onset of Ersexpressionis crucial in establishing a correctly polarizedmidbrain27. The deletion of the midbrain followingthe removal of all En function means that such mutants are of little use in analysingthe later function of En. Hence, other methods such as transplantations, retroviral infection and antisense approaches were required to understand the importance of En in axonal patterning. When the mesencephalic alar plate, a region of the primordial tectum, is transplanted to the forebrain, an ectopic or ‘diencephalictectum’ with typical lamination develops,expressesEn, and receivesretinal innemationzg,zg. The correlation between innervation and En expression suggeststhat En could be involved in the regulation of tectum as a retinal target (see Fig. 1). However,in antisense experiments where Ers expression is inhibited after early specification of the mesencephalic neuroepithelium as tectal but before the development of the retinal projection, retinal axons find and enter the En-depletedtectum30.This suggeststhat although early En expression might be involved in the generation of the tectum as a retinal target, continued En expression does not regulatethe local cues that tell retinal axons they have reachedthe tectum. -ErzgraiZed expression in postsynaptic cells does not correlate strictly with retinal innervation, as rostral tectal cells have very low levels of Ersexpression, and cerebella cells, which are not innervated by the retina, have high levels of En expression.The level of highest En expression might in fact be repulsive to certain axons. The axons of the intertectal commissure,for example, connect one tectal lobe to the other topographically across the whole of the tectum. However,these axons avoid the posterior pole of the tectum, the region of highest Ersexpression. In Endepleted brains, these axons no longer avoid this region30,suggestingthat the continued expression of En might regulate a repulsivemolecule that patterns

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Fig. 1. Axons fallow local positional information in the brain. (A) AxorJs fdowpositionalin connation rdong the optic tract. The domains of expression of some known homeobox genes are indicated on a schematic lateral view of a Xenopus brain. The optic tract (black line) fo//ows a stereotyped route from the eye to the tectum, turning posteriorly at mid-diencephalon. The positional information encoded by homeobox genes could be read like a multicolored map bypath finding axons, Abbreviations: Di, diencephalon; Mes, mesencephalon; Met, metencephalon; Tel, telencephalon. (B) Axons follow positional information in the tectal target. The retinotectal projection follows topographic order, such that nasa/ (N) retinal cells project to posteriar (P) tectum, whereas temporal (T) retinal cells project to anterior (A) tectum. (C) The Engrailedgradient in the tectum. Top view ofa Xenopus brain stained for ENGRAILED with the aEnhb-7 po/yc/ona/ antibody recognizing both ENI and EN2 proteins, and centered on the midbrain (rob). The expression is strong at the isthmus and decreases anteriorly towards the diencephalon and posteriorly towards the hindbrain (hb). Scale bar, 700pm.

the tectum internally with respect to axonal growth, and provideslocal positional information within the tectum. Engrailed and retinotectalpattern

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levels of ectopic En expression in regions throughout the tectum. In these brains, nasal fibers (which normally recognize the En-high posterior tectum) arborizeciat ectopic sites in anterior tectum, and temporal fibers (wh;ch normally recognize the En-1ow anterior tectum) failed to innervate or degenerated~z (Fig. 2(;’). This last series of experiments shows that the En expressionlevel is linked tightly to retinotopy, and suggestsstronglya causalrelationshipbetweenEn and retinal topography. Since E;N itself, being a nuclear transcription factor, cannot act directly as local guidance c“ue,the question arises: what are the local cues downstreamof EN? The realisatorsof the retinotopicmap might be Engrailed targets

In the past year or so, four serious candidate effecter moleculesthat could directlyinfluence the growth cones of retinal axons in the rostrocaudalaxis of the tectum have been characterized: ELF-1, RAGS,TOP,P and RGM (Fig. 3). ELF-1and RAGSare ligands for the Ectopic tectum with inverted 1%polarity growing Eph family of receptor tyrosine kinases (for Retina reviews,see Refs 34,35) and the others are membrane proteins. Ectopic En TOP,,,,is an integralmembraneproteinwith a coiledEndogenous En I I coil structureand a leucine-zipperdomain susceptible to protein-protein interactions;’;.It also sharesregions bicaudal of sequence similarity with the LMsophila protein (involved in antero-posterior polarity in the embryo). Levels of TOP,i[,are 16-fold higher in the temporal than the nasal retina, and eightfold higher in the rostral than the caudal tectumJ7. ELF-1 and RAC;Sare glycosylphosphatidylinositol(GPI)-anchored Retina Tectum ligandsfor the Eph family of receptortyrosine kinases, Fig. 2. Engrailed, tectal pokm’ity and retinotopy. (A) Transplantation of rnesencephcdic and a~re,opposite to TOP,,,,,expressedin caudal-high to rostral-lowgradientsin the tectums8{9.The receptor (Mes) a/ar p/ate into chjck djencepha/on (Di) produces an ectopic tectum with inverted po/arity. Engrailed (En) expression k found as a norma/ postero+wrteriorgradient in tfre tectum and for ELF-1, named Mek4, is converselyexpressedin an as an inverted antero–posterior gradient in the ectopic ‘diencephalic tectum’. (B) In ectopic increasing naso-temporal gradient in the retina and tecturri with inverted po/arity, retkrci axons follow a new topographic order. Nasal (IV) fjbers on optic axons~[’. Functional analysis for RAGS innervate the regjon of high En expression, and temporal (T) fjbers innervate the region of low shows that this ligand is indeed a repulsivemolecule En expression. (C) Ectopic En expression jn the anterior tectum causes nasa/ fibers to arborize to retinal axons]g. ELF-1, when assessed for in vitro at ectopic sjtes. Ectopic En expression is obtained by infecting chicks of one speck’s with a retroguidance or for in viva mapping in retrovirally overvkus of a limited host range engineered to expres En, and then transp/antjrrg krfected tecta/ expressing tecta, shows a strong topographic specicc//s krto a resistant host strain, Nasa/ fibers innervate high En-expressing lregions in the ficityto repulsetemporalaxons”. RGM(repulsiveguidanterior (A) tectum, and temporal fibers fail to irv)ervcrte or degenerate (broken line). ing molecule)is a GPI-linked33 kDa protein~zpurified on the basis of its ability to repel temporal axons in a midbrain;’ and in a decreasinggradient anteriorly:~’zz stripe assay4:+ consisting of alternating stripes of ante(Fig. IC). Assketchedin Fig. 2, the workof Itasakiand rior and posterior tectum. Recent chromophoreNakamura has dem
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33kDa ‘m Fiq. 3. Possible realisators of the retirrotaDic map. Newly discovered or characterized molecules expressed as grodients in the retina, tectum, or both, are indicated. Mek4 is expressed on retinal cells and is the receptor tyrosine kinase for the ELF-1 Iigand which is expressed as a motching gradient on tectal cells. RAGS (for repukive axon-guidance signal) is a Iigand for the scrme Eph-re/ated fami/y of tyrosine kinase receptor as ELF-7, but its receptor is not characterized yet. TOP~P is expressed both in the retina and the tecturn, and could be used for homophilic interaction. The33 kDaprotein,or RGM (for repu/siveguidance me/ecu/e), was purified on its ability to repulse temporal axons. TRAP is expressed only in the temporal retina.

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of both RAGSand ELF-1, and makes mis-expressing 1 1 tectal membranes inhibitory to temporal axons45. Thus, these molecules are regulatedby En. It is not yet Fig.4. Upstreamanddownstream of Engrailed.(A) Positive and negative influences on the clear, however, whether they are direct targets such expression of Engrailed(En) come from various parts of the embryo. Schematic drawing of a that the ENprotein binds to their upstreamregulatory lateral view ofa chick brain where the positive influences on Enexpression ore depicted in green regions. This can be addressedby the various tech- and the negative influences are depicted in red. The isthmic region and the cardiac mesodenn niques available to search for in vivo targets of tran- (Meso) underlying the origina/ region of En expression are two strong positive regulators of En. scription factors and promoter analysis. In any case, The dierrcephalic-mesencephalic (Di-Mes) boundary, the floarplate and notochord have negative this resultconstitutes a formal demonstrationthat the influence on Enexpression. The grading across the mesencephalon represents the Engradient. En homeobox gene governs the local expression of (B) Hypathetica/ signaling cascade of the tectal map. Engrailedis seen as the centra/ regu/ator of the tectcd map, with all its related regulators and effecters. Re/atianships ore indicated axon-guidancemolecules. with dotted /ines when not proven to be direct, and with a question mark when hypothetical.

Tracingthe originsof the retinotectalpattern

If ELF-1, RAGSand others do turn out to be direct downstream targets of En, then part of the puzzleis solved, that is, we will understand how it is that locally expressed homeobox genes can lead to the expressionof locally expressedguidancecuesto which axons can respond in the embryonic neuroepithelium. The next question is how is it that the En gradientgets establishedproperlyin the first place? In the signaling cascade that establishes tectal polarity, the En gradient itself is under the control of other molecules acting earlier in development or higher in the patterning cascade (Fig. 4). These molecules originate from different regions. The diencephalicmesencephalic junction has a negative influence on En expression. This was demonstratedin experiments in which En expression in posterior midbrain was downregulatedwhen it was transplanted next to the diencephalic–mesencephalic junction28. The floor plateand notochordalsosuppressEn expression,as seen when En-expressingmidbrain is transplantednear this tissue46.There are also local interactions that seem to induce Ers expression, a planar signal that moves through the extending neural plate and a vertical signal arising from the anterior portion of the chordomesoderm47.Interestingly, the region of the brain

with the strongestEn-inducingcapacityis the isthmus where En is most highly expressed.When this region is transplanted by itself it induces En expression in nearbytissue and can induce an entire ectopic tectum out of forebraintissue, acting as a sort of organizer23. The isthmus also expresses the secreted molecule WNT1, the vertebrate homolog of the Drosophila segment polarity gene product WINGLESS(WG), the best known regulatorof en expression (for review,see Ref.48). In Drosophila, wg is cruciallyimportant for the normal expression of en. It is not clear whether WG protein acts as a morphogen along a concentration gradient or as a local signal affecting only adjacent cells49,since en expressionis also critical for wgsignaling. In Wntl knockout micesoor in wg mutants in Drosophila51’5z) animals progressivelylose an originally normal Ersexpression.This suggeststhat Wntl is not involved in En induction, but rather in its maintenance in adjacentcells.This maintenancein Drosophila involvesa cascadeof signalingevents including genes such as porcupine(another segment polarity gene) in the wg-expressingcell, armadillo (a homolog of b-catenin),dishevelledand shaggy(homolog of glycogen synthasekinase3b) in the wg-responsiveen-expressing cell. TLVSVO1. 19, No. 12,1996

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REVIEW Recently, FGI%, ar]other secreted factor expressed first in the mesodern]and then in the overlying isthmus, has been show]-to have midbrain-inducingand polarizing effects’+. Beads soaked in FGF8 induce ectopic E}? and Wrr[1 expression in the caudal diencephalon and cause a mirror-imageduplication of the mesencephalon.‘{’hefact that FGF8is sufficientto induce E}?expression-;,together with the observation that FGF8 is expresw:din mesoderm underlying the neural plate at a stag(’before Erzinduction, raisesthe possibility that me>oderrnal FGFt3 could be the inducer of isthmic E/,expression. That a secreted signal like FGF8 can induce Err expression does not, of course, tell how direct this regulation is, and the timecourse of Et?expression following implantati,m of FGF8-soakedbeads indicates that it is probablyindirect. It is possiblethat this FGF8 activates anott]er locally expressed homeobox transcription factor wch as Pax2 which is expressed expression at the just prior to E)} ;Irrd Wr/fl midbraimhindbrain junctiom~’. Indeed, zebrafish embryos injected with anti-Paxb (the probable zebrafishhomolog of murinePux2)showdecreasedEI~ and W/rflexpression’. Consistentwith this possibility is a recent analysisof !he .0) gene regulatorysequences showing severalcons(nsus Pax-bindingsitess(’. It is not known hotv the pattern of Fg/%’ expression in the mesodermis I .gulated. This might be the next quest in an iterativ~ series that eventually takes us from the local guidal~cecues in the tectum back to the origins of embryonit axis formation. Such questions imply that we have .eached a time in the history of neurobiology where we can begin to piece together the developmental /ogic of neural wiring, starting from positional infoirnation in the egg and ending with topographic mal)Sin the adult brain.

9 ILubenstein, J.L. et al. (1994) .scieli[e 266, S78-580 Pudlcs, L. and Rubenstein, J.L. (1993) Trends Neurmc-i. 16, 472--479 11 Figdor, M.C. and Stern, C.D. (1993) Nature .363, 630-634 12 Boncinelli, E. (1994) Cf{rr. Opif~,Nt,rmobiol.4, 29–36 13 Wilson, S.W., Placzek, M. and Furlcy, A.J. (1993) Trends Neumsci. 16, 316323 14 Macdonalct, R. et al. (1994) Nfuron 13, 1039-1053 15 Macdunald, R. et cd. (1995) Deve/opww)il 121, 3267–3278 16 Morata, G. and I.awrence, P.A. (1975) Nafure 255, 614-617 17 Kornberg, ‘I’. (1981) Proc, ,Vat[. Acud. Se-i.U. S. A. 78, 1095–1099 18 Patel, N.H. et aL (1989) Ce[[ 58, 955-968 19 Juyner, A.I.. et a/. (1985) Cell 43, 29-;7 20 Alvarado-Mallart, ELM., Martinez, S. and Lance-Jones, C.C. (1990) Dev. Bid. 139, 755-788 21 Davis, A.C. et al. (1 991) Dew/opmeM 111, 287-298 22 Hemmati-Brivanlou, A. et al. (1991) Ocvdopmwt 111, 715-724 23 Martinez, S., Wassef, M. and Alvarado-Mallart, R.M. (1991) Nc[/wtI 6, 971-981 24 Wurst, W., Auerbach, A.B. and ,Joyner, A.L. (1994) f)W[>/OfHWZt 120, 20(>5-2075 25 Joyner, A.I,. ( 1996) Tre)l[ls GeIIel. 12, 15-.20 (1991) Sc-ietlcf,251, 12:j9-1243 26 Joyner, A.L. etal. 269, 679--682 27 Hanks, M. etal. ( 1995) .SCierI[-e (1991) Deve/opwent 113, 1133-1144 28 Itasaki, N. etal. 29 Itasaki, N. and Nakamura, H. (1992) Neuron 8, 787–798 30 R&mxr S., McNeill, L.M. and Harris, W.A. (1 996) Neuron 16, 6:<-7S 31 Joyner, A.L. etal. (1985) Ct>/l43, 29-37 32 Itasaki, N. and Nakamura, H. (1996) N[,urol] 16, 55-62 33 Friedman, G.C. and 0’I.eary, D.D.M. (1996) J. Neurosci. 16, 5498-5509 34 Harris, W.A. and Hult, C,E. ( 1995) Ne[[rorf 15, 241-244 35 ‘l’essier-Lavigne, M. (1995) Ce[[ 82, :345-348 36 Savitt, J. M., Trisler, D. and Hilt, DC. (1995) Neuron 14, 25:3--26 1 37 Tris’ler, D. (1990) ). Exp. Bio/. 153, I 1-27 38 Chcng, H.J. and FIanagan, J.G. (1994) Ce[/ 79, 157-.168 39 Dre:;cher, U. et a[. (1995) Cell 82, 359-370 40 Cheng, H.J. et al. (1995) (1’// 82, 371-381 41 Nakamoto, M. etal. ( 1996) Cc// 86, 755-766 42 Stahl, B. et cd. (1990) Nefo’of~5, 735-743 43 Waltcrj J., Henke-Fahle, S. and Bonhoeffer, F. (1987) Dwdoptnerit 101, 909-913 44 Muller, B. K., Jay, D.F. and Bonhoeffer, F. (1995) SO(.Neur-mci. Ahfr. 21, 292 45 Logan, C. et al. (1996) (:[/i’r. Bio/. 106, 1006-1014 46 Darnell, D.K. and Schoenwolf, G.C. (1994) }. Ne//rohiol, 26, 62-74 Selected references 1 ‘1’aylor, J.S.H. (1990) 1, v<,[qvnmt 108, 147–158 47 Hmnmati-Brivanlou, A., Stewart, R.M. and Harland, R.M. 2 Harris, W.A. (1989) N.fure 339, 218-221 (199’0) Sticnce 250, 800-802 48 Klingensmith, J. and Nussc, R. (1994) D(w. Biol. 166, 496-414 3 Sperry, R.W. ( 196:3) Pwc-.Nut/. ,4cud. .Sci,U. S. ,4.50, 703-710 116, 4 Gould, A.P. and IVhite, R.A. ( 1992) Dctwloprrferit 49 Vincent, J.P. and Lawrence, P.A. (1994) Nat[re 372, 132-133 11(1+-I 174 5(J Mci?4ahon, A.P. et al. (1 992) Cdl 69, 581-.59S 5 Edehnan, G.M. and .lonm, k..S (1995) P1/i/a$. ‘lm)f.s. R. SOC-. 51 Martinez-Arias, A., Baker, N.E. and Ingham, P,W. (1988) Lo)f,/(vf Sfr. tr 349, 305 .ilz Devc/opmefl( 103, 157-170 (19{)2) Proc. Nat/. AC-ad. Sri. IJ, ,S. A. 89, 6 Jones, F.S. etal. S2 DiNardo, S. et al. (1988) Nati/re 3.32, 604–609 209-2095 53 Crosslcy, P. H., Martinez, S. and Martin, G.R. (1996) Nature 7 Jones, F’.S. et cd. ( 1[)’)2) /)rm’. Nat/. Arad. .Sci. IJ. S. A. 89, .380, 6(>-68 2086-2090 54 Rowitch, D.H. and McMahon, A.P. (1995) Me(-/].Dev, 52, 3–8 8 Rubenstein, J.L. and I’uelles, I.. (1994) Curr, Top. Dev. Bid. 29, 55 Krauss, S. et af. (1992) Nature 360, 87-89 1-():3 56 Song, D.L. et a/. (1996) IX)w/op/nerZt 122, 627-635 10

Articles of interest in the other Trends journals Botulinum neurotoxins: mechanism of action and therapeutic applications, by Cesare Montecucco, Giampietro Schiavo, Valeria Tugnoli and Domenico de Grandis Molecu/or Medicine Today 2, 41 8+24 Large clostridial cytotoxins – a family of glycosyltransferases modifying small GTP-binding proteins, by Christoph von Eichel-Streiber, Patrice Boquet, Markus Sauerbornn and Monica Thelestam Trends in Microbiology 10, 375–382 Expression of complement in the brain: role in health and disease, by B. Paul Morgan and Philippe Gasque Immunology Today 17, 461-466 Language and psychosis: common evolutionary origins, by T.J. Crow Endeavour 20, 105-109 Synaptic pror.eins and the assembly of synaptic junctions, by Craig C Garner and Stefan Kindler Trends in Cell Biology6, 429-433 —

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