Brain Research Bulletin 66 (2005) 297–302

Expression patterns of developmental regulatory genes show comparabledivisions in the telencephalon ofXenopusand mouse: insights into the

evolution of the forebrain

Loreta Medina∗, Aurora Brox, Isabel Legaz, Margarita Garcıa-Lopez, Luis PuellesDepartment of Human Anatomy, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain

Available online 24 February 2005

Abstract

In this study, we review data on the existence of comparable divisions and subdivisions in the telencephalon of different groups of tetrapodsbased on expression of some developmental regulatory genes, having a particular focus in the comparison of the anuran amphibianXenopusandthe mouse. The available data onXenopus, mouse, chick and turtle indicate that apparently all tetrapod groups possess the same molecularlydistinct divisions and subdivisions in the telencephalon. This basic organization was likely present in the telencephalon of stem tetrapods.Each division/subdivision is characterized by expression of a unique combination of developmental regulatory genes, and appears to representa rpretationh consideredh mparable( enarios ofe . Finally,a tes, raisingi©

K

1

bstimgbehta

om-n ofandf

ech-r thetand-lar,len-dingthe

6]lianaus-and,

0d

self-regulated and topologically constant histogenetic brain compartment that gives rise to specific groups of cells. This inteas an important consequence for searching homologies, since a basic condition for cell groups in different vertebrates to beomologous is that they originate in the same compartment. However, evolution may allow individual cell groups derived from cofield homologous) subdivisions to be either similar or dissimilar across the vertebrate groups, giving rise to several possible scvolution, which include both the evolutionary conservation of similar (homologous) cells or the production of novel cell groupsvailable data in the lamprey, a jawless fish, suggest that not all telencephalic subdivisions were present at the origin of vertebra

mportant questions about their evolution.2005 Elsevier Inc. All rights reserved.

eywords: Ventral pallium; Lateral pallium; Claustrum; Pallial amygdala; DVR

. Introduction

The telencephalon is the most rostrodorsal region of therain and contains the superior centers involved in control ofensorimotor, autonomic and endocrine functions, in emo-ional behavior, as well as in cognitive functions such as learn-ng and memory. Classical studies established that in mam-

als the telencephalon contains the cerebral cortex, the basalanglia, the claustrum, the amygdala, the septum and otherasal forebrain areas that include the basal nucleus of Meyn-rt. For more than a century, comparative neurobiologistsave tried to unravel the evolutionary origin of these struc-

ures and to find their homologues in other vertebrates, withparticular focus in the cerebral cortex and basal ganglia.

∗ Corresponding author. Tel.: +34 968 364340; fax: +34 968 363955.E-mail address:lmedina@um.es (L. Medina).

This task turned out to be extremely difficult due to the cplex and apparently variable morphological organizatiothe diverse cell groups in the telencephalon of mammalsnon-mammals (for review, see[62]). With the development ohistochemical/immunohistochemical and tract-tracing tniques and their use by comparative neurobiologists aftelate 1960s, major advances were achieved in our undersing of the organization of the telencephalon. In particuthe basal ganglia could be identified consistently in the tecephalon of several non-mammalian vertebrates, inclubirds, reptiles, amphibians and jawed fish, as well as inlamprey, a jawless vertebrate[26,29–31,39,42,43,50,51,6.However, the origin of other parts of the mammatelencephalon, including the cerebral cortex, the cltrum and the amygdala, remains partially uncertainideas on their evolution are still controversial[1,15,25,4549,62].

361-9230/$ – see front matter © 2005 Elsevier Inc. All rights reserved.oi:10.1016/j.brainresbull.2005.02.003

298 L. Medina et al. / Brain Research Bulletin 66 (2005) 297–302

The discovery of developmental regulatory genesinvolved in brain patterning, regional specification andmorphogenesis, and their use by comparative developmentalneurobiologists have opened new scenarios for studies ofbrain evolution[2,3,8,9,19,20,34,48]. Developmental regula-tory genes encode signaling proteins or transcription factorsthat regulate the expression of other genes, and are involvedin different aspects of development, including patterning,specification, cell proliferation (growth) and cell differ-entiation. These genes show highly conserved sequencesand positionally stereotyped expression patterns, and havebecome very useful tools for comparing brain regions acrossvertebrates. Here, we review recent evidence suggesting thatin tetrapods the telencephalon consists of the same basichistogenetic divisions/subdivisions, which are characterizedby expression of unique combinations of developmentalregulatory genes[2,3,8,9,19,20,32,34,48]. This approach hasallowed more precise identification of homologous pallialsubdivisions inXenopus, sauropsids and mouse, supporting afundamental subdivision of the conventional lateral palliuminto novel lateral and ventral pallial sectors[48]. Theselateral and ventral pallial subdivisions give rise to parts ofthe piriform cortex, claustrum and amygdala in mouse, andwe discuss whether similar cell groups are produced in thecorresponding pallial subdivisions ofXenopus.

2dp

ent,t ajorm ium[ ss atoryge sD alg diala someb cleuso d thecpi neL rum,p andt ptum[ si eseg ce inp lliuma

dedi -

ple, the subpallium includes striatal, pallidal and anteriorentopeduncular subdivisions showing expression of distinctcombinations ofDlx2/5, Nkx2.1 andSonic hedgehoggenes[44,48,56,63]. The pallium, classically divided in three parts,also can be subdivided by differential expression of severaldevelopmental regulatory genes, includingLmo2, Emx1 andLmo3 [10,48,65]. The LIM-only genesLmo2 andLmo3 areexpressed strongly in either the medial (hippocampal) or thelateroventral (piriform lobe) pallial territories, respectively,but their expression is weak in the dorsal pallium[10,65].Other developmental regulatory genes are expressed acrossthe pallium in gradients: for example,Emx2 andPax6 areexpressed in opposing gradients in the pallium, from caudo-medial to rostrolateral levels or viceversa[4,5], and the LIMhomeodomain geneLhx2 is expressed strongly in the dor-somedial pallium, gradually diminishing into the lateroven-tral pallium [10,52]. The three pallial territories are dif-ferently affected by mutations targeting distinct regulatorygenes involved in pallial development. For example, in theabsence of the LIM homeodomain geneLhx2, the medialand dorsal pallial sectors are severely shrunken[10,65]. Incontrast, the piriform lobe, as characterized by its normalmarkersLmo3 and Dbx1, appears relatively normal-sized(see below[65]). This suggests that these subdivisions areself-regulated histogenetic compartments, whose distinct de-velopment is controlled by specific networks of regulatorym opu-l t” in[

inm d thee ba-s ep sop ter-m asp pal-lt tedt onie ml ven-t at-e ”).Ba iaa om-pa olat-e dalara wo ralp rum,e ba-

. Telencephalic divisions/subdivisions and theirerivatives in mouse based on gene expressionatterns

A large amount of data indicates that, during developmhe telencephalon in mouse becomes divided into two molecularly distinct domains: the pallium and the subpall

11–13,16,32,46,48,60,64,67]. These two major divisionhow distinct expression of several developmental regulenes and give rise to different cell groups (Fig. 1(A)). Forxample, the subpallium expressesDlx family genes (such alx1, Dlx2 andDlx5) andGsh1/2, and gives rise to the basanglia, part of the amygdala (including the central, mend intercalated nuclei), a major part of the septum, andasal telencephalic cell groups that include the bed nuf the stria terminalis (BST), the extended amygdala anorticopetal cholinergic neurons[12,32,48,64,67,68]. Theallium expressesPax6, Emx1/2, Neurogenin2, T-brain fam-

ly genes (Tbr1 andTbr2), and the LIM homeodomain gehx9, and gives rise to the cerebral cortex, the claustart of the amygdala (including the basolateral complex

he cortical amygdalar areas) and a small part of the se4,5,11,13,23,32,48,52,57,58,60,61,64,68]. Several studienvolving lack-of-function of a single gene or a pair of thenes (using knockout mice) have shown their importanatterning and morphogenesis of the telencephalic pand subpallium (for example,[4,5,35,61,64,67,68]).

Both pallium and subpallium can be further subdivinto smaller molecularly distinct domains[48]. For exam

olecules, and which give rise to specific neuronal pations (see discussion of the concept of “compartmen47]).

In addition to the classical subdivision of the palliumedial, dorsal and lateral domains, Puelles et al. propose

xistence of a distinct ventral pallial subdivision on theis of differentialEmx1 expression: while the majority of thallium expresses stronglyEmx1, the ventral pallium shownly someEmx1 signal at its pial surface[48] (this territoryoor in Emx1 was previously described and named “inediate zone”[59]). Puelles et al. included this territoryart of the pallium based on its expression of typical

ial marker genes, such asTbr1 in the mantle andPax6 inhe ventricular zone[48]. Later studies have corroborahe existence of a distinct ventral pallial territory basedts selective expression of the homeobox geneDbx1 duringarly development[32,68]. As a result, the classical pirifor

obe includes two subdivisions, a lateral pallium and aral pallium (this involves a re-definition of the classical “lral pallium”, which used to include all the “piriform lobeased on differential expression ofEmx1,Cadherin8 (Cad8)ndSemaphorin5A (Sema5A), the lateral and ventral pallppear to give rise to different parts of the claustral clex and pallial amygdala[32,48]. Thus, the lateral palliumpparently gives rise to the dorsolateral claustrum, basral amygdalar nucleus and posterolateral cortical amygrea (all showing highEmx1 andCad8 expression, but lor no Sema5A signal) [32]. On the other hand, the ventallium appears to give rise to the ventromedial claustndopiriform nuclei (except a posterior part), lateral and

L. Medina et al. / Brain Research Bulletin 66 (2005) 297–302 299

Fig. 1. Diagrams showing the telencephalic divisions and subdivisions in tetrapods (A) or fish (B). As shown in (A), each telencephalic division/subdivisionshows expression of a unique combination of developmental regulatory genes. Many of the genes represented have been analyzed in mouse, chick andXenopus(Dlx/Dll , Nkx2.1,Sonic hedgehogorShh, Pax6,Tbr1/2, andEmx1). Some of these have also been analyzed in turtle (Dlx, Pax6,Emx1). Their expression patternsin the different species, in combination with other anatomical and molecular data, suggest that all tetrapods show the same (field homologous) molecularlydistinct divisions and subdivisions in the telencephalon. Some of the genes shown in (A) have only been analyzed in mouse (Dbx1, Lmo2, Lmo3) and morestudies are needed in non-mammalian species. Based on expression ofDistal-less(Dll ) andPax6, it appears that the major telencephalic divisions (palliumand subpallium) are present in fish (including jawed fish, such as the teleost zebrafish, as well as some jawless fish, such as the lamprey). Based on expressionof Nkx2.1, zebrafish appears to have striatal and pallidal subdivisions in the subpallium, but the lamprey apparently lacks such subpallial subdivisions.In thepallium, the expression pattern ofEmx1 suggests the existence of a ventral pallial subdivision in fish (including the lamprey). The existence of a medial palliumhas also been proposed in teleosts based on other criteria (topological position, connections, function). However, the existence of other pallial subdivisions is atpresent unclear. See text for more details.Abbreviations: AEP, anterior entopeduncular area; DP, dorsal pallium; LP, lateral pallium; MP, medial pallium; PA,pallidum; ST, striatum; VP, ventral pallium.

somedial amygdalar nuclei, plus the anterior and posterome-dial cortical amygdalar areas (all showing moderate to highsignal ofSema5A but no expression ofEmx1 andCad8) [32].Below we analyze whether these basic divisions/subdivi-sions are found in the telencephalon of non-mammalianvertebrates, and whether they give rise to comparablecell groups.

3. Telencephalic divisions/subdivisions inXenopusand comparison with those of the mouse and othervertebrates

The telencephalon of the anuran amphibianXenopusshows the same major divisions (pallium and subpal-lium) characterized by differential expression of the sameregulatory genes described in the mouse[3,8,9,40]. The

same molecularly distinct divisions are also found inthe telencephalon of turtle and chick[48,59], suggestingthat this basic organization is common to all tetrapods(Fig. 1(A)).

As found in mammals, birds and reptiles[48,59], thesubpallium ofXenopusexpressesDistal-lessfamily genes[3,8,40] and gives rise to the basal ganglia (as identified in[29]), part of the amygdala (including the so-called anteriorand central amygdalar nuclei) and some basal telencephaliccell groups that include the BST and the basal cholinergiccells [8]. Within the subpallium, striatal, pallidal and possi-bly anterior entopeduncular divisions showing distinct nestedexpression ofDistal-less, Nkx2.1 andSonic hedgehogmarkergenes appear to exist inXenopus[3,7,8,19,20].

On the other hand, as in mammals and birds[13,48], thepallium of XenopusexpressesPax6 andTbr family genes(Tbr1 andEomes/Tbr2) during development[3,9]. Further,

300 L. Medina et al. / Brain Research Bulletin 66 (2005) 297–302

recent studies indicate that the pallium ofXenopusincludesa previously unrecognized ventral subdivision showing poorEmx1 signal, which resembles the ventral pallium of mouseand chick[3,8,9]. This ventral pallial subdivision also appearsto express a unique combination of LIM homeodomain genessuch asLhx2, Lhx9 andLhx5 [34]. While this ventral pallialsubdivision identified inXenopusis comparable to the ventralpallium of mouse, chick and turtle in terms of topology andmolecular specification, more studies are needed to confirm towhat extent these ventral pallial territories are field homolo-gous. Another complementary question is to understand howsuch homologous regions can apparently differ so much insize, morphology and function in different lineages (i.e., theventral DVR of birds and reptiles, and the ventral subdivisionof the pallial claustroamygdaloid complex of mammals). Ifmorphological diversity is the result of quantitative or quali-tative changes in the genetic regulatory programs that operatein development[17,18], we need to find out what are the keygenes that control the specification and morphogenesis of theventral pallium, and to understand what is different in thegenetic regulatory cascades that control the development ofthis territory in different tetrapods.

According to our data, the lateral and ventral pallial sub-divisions of Xenopusinclude dorsal and ventral subdivi-sions of the classical piriform lobe (as the case in othervertebrates), and contain superficial olfactorecipient fieldst iotes[p plexot ralp ma-j la xons[ rto l in-p alara ntralp sw me-d l-o als[ me-d eaki -t tes[a omeb l pal-l meo ntralp rdsa e cellg lianc ringe

4. Molecular divisions/subdivisions in thetelencephalon of non-tetrapods

Molecularly distinct pallial and subpallial domains arepresent in the telencephalon of jawed fish (for example, theteleost zebrafish) and in the lamprey, a jawless fish whoseancestors are close to the origin of vertebrates (Fig. 1(B))[22,36,66]. As in tetrapods, the subpallium of zebrafish andlamprey is characterized byDistal-lessfamily genes, whereasthe pallium of these animals expressPax6 andEmx. Thesubpallium of zebrafish also appears to show a subdivisionthat expressesNkx2.1, suggesting that the subpallium of thisjawed fish may have striatal and pallidal subdivisions likethose of tetrapods[54]. However, expression ofNkx2.1 hasnot been reported in the basal telencephalon of the lamprey,raising a doubt on the existence of a pallidum in these an-imals (this gene is calledTTF-1 in [36]; see also[42,43]).Also, it is unclear whether zebrafish has an anterior entope-duncular subdivision in the subpallium, since no expressionof Hedgehogwas observed in the telencephalon in this teleost[22,24]. On the other hand, in the lamprey the pallium showsa relatively large potential ventral pallial subdivision, poor inEmx1 [36]. However, the existence of further molecular sub-divisions in the pallium of these jawless animals and in jawedfish remains unclear. A medial pallium may be present insome fish (such as zebrafish, based on topological location,1

c l-l eo sub-p stralfi divi-s romj n thes ex-a e pal-l rentd f dif-f ededt

i senti verye tantv podsc toryb la).L toryb andt s, iti atesc pre-s lliala hat

rt oft

hat have been compared to the piriform cortex of amn38,62]. In addition, the lateral and ventral pallia ofXeno-usinclude different parts of the amygdalar nuclear comf amphibians, as identified by Marın et al. [9,29]. Thus,

he ventral pallium ofXenopusappears to include a rostart of the so-called lateral amygdalar nucleus and a

or part of the medial amygdalar nucleus[9]. The mediamygdalar nucleus is the major target of vomeronasal a

33,38,55]. If the ventral pallial origin of a significant paf this nucleus is confirmed, its important vomeronasaut makes it similar to the posteromedial cortical amygdrea of mammals, which as noted above is also a veallial derivative (discussed in[9]). Further investigationill be required to discriminate whether a part of theial amygdalar nucleus ofXenopusis subpallial and homogous to a similar part of the medial amygdala of mamm

33,34]. On the other hand, both the rostrolateral andial amygdalar nuclei of anuran amphibians receive w

nput from collothalamic nuclei[33,37], a hodological feaure typical of specific ventral pallial cell groups of amnio14,15,21,27,28,45]. Thus, the ventral pallium ofXenopus,s defined molecularly, contains cell groups that show sasic connections similar to those typical of some ventra

ial cell groups of amniotes, raising the possibility that sof these groups may be homologous. However, the veallium evolved into a very large territory in reptiles, bind less so in mammals, and it is conceivable that somroups found in the avian/reptilian DVR or in the mammalaustroamygdaloid complex have arisen de novo duvolution.

onnections and functional studies[6,53]), but a dorsal paium may be absent in lampreys[41] and perhaps in somther fish groups. Thus, although the major pallial andallial telencephalic divisions were likely present in ancesh close to the origin of vertebrates, some of the subions may have originated in concert with the transition fawless to jawed vertebrates (for example, the pallidum iubpallium), or in the transition from fish to tetrapods (formple, the anterior entopeduncular area, or perhaps som

ial subdivisions). More studies on the expression of diffeevelopmental regulatory genes in the telencephalon o

erent fish groups and in non-anuran amphibians are neo try to fix when each telencephalic subdivision arose.

Nevertheless, based on differential expression ofEmx1,t appears that a ventral pallial subdivision is pren lampreys and tetrapods, and possibly originatedarly in vertebrate evolution, being present in most exertebrates. As noted above, the ventral pallium of tetraontains several areas receiving input from the olfaculb (the piriform cortex and parts of the pallial amygdaampreys and jawed fish have relatively large olfaculbs and massive olfactory projections to the pallium,his was likely the ancestral condition. Considering this plausible that the ventral pallium of ancestral vertebrontained specific olfactory-recipient areas that may reent precursors of the piriform cortex and olfactory pamygdala of tetrapods. Still, it is important to know w

1 In zebrafish, the medial pallium is located in the lateral or distal pahe pallium due to its eversion during development.

L. Medina et al. / Brain Research Bulletin 66 (2005) 297–302 301

is different in the molecular programs that operate duringdevelopment of the ventral pallium in different vertebrategroups. In this sense, it is interesting to note that, contrary tothe ventral pallium of the mouse, the presumed ventral pallialterritory of zebrafish does not expressDbx1a [24]. It is alsounknown whetherDbx1 is expressed in non-mammaliantetrapods (reptiles, birds and amphibians). Future studieswill need to address this question and to investigate the rolethat this gene plays in ventral pallial development.

Acknowledgements

This work was supported by the Spanish Ministry ofScience and Technology (CYCIT-FEDER; Grants BFI2000-1359-C02-02 and BFI2003-06453-C02-02 to L.M.; fellow-ship FP2000-5943 to I.L.), the Spanish Ministry of Health-Institute Carlos III (Grant FIS-FEDER 01/0057-02 to L.M.and Red CIEN-Nodo 318) and Seneca Foundation (GrantPB/50/FS/02 to L.M.).

References

[1] F. Aboitiz, D. Morales, J. Montiel J., The evolutionary origin ofthe mammalian isocortex: towards an integrated developmental and

m-7

ilyithi. 21

.D.ina-and360.en-

0)

the995)

-iver-

nes

003)

nesss, J.

[ ainev.

[ N.pat-

ain

[12] A. Bulfone, L. Puelles, M.H. Porteus, M.A. Frohman, G.R. Martin,J.L.R. Rubenstein, Spatially restricted expression ofDlx-1, Dlx-2(Tes-1), Gbx-2, andWnt-3 in the embryonic day 12.5 mouse fore-brain defines potential transverse and longitudinal segmental bound-aries, J. Neurosci. 13 (1993) 3155–3172.

[13] A. Bulfone, S.M. Smiga, K. Shimamura, A. Peterson, L. Puelles,J.L.R. Rubenstein,T-Brain-1: a homolog ofBrachyury whose ex-pression defines molecularly distinct domains within the cerebralcortex, Neuron 15 (1995) 63–78.

[14] A.B. Butler, The evolution of the dorsal thalamus of jawed verte-brates, including mammals: cladistic analysis and a new hypothesis,Brain Res. Brain Res. Rev. 19 (1994) 29–65.

[15] A.B. Butler, The evolution of the dorsal pallium in the telencephalonof amniotes: cladistic analysis and a new hypothesis, Brain Res.Brain Res. Rev. 19 (1994) 66–101.

[16] K. Campbell, Dorso-ventral patterning in the mammalian telen-cephalon, Curr. Opin. Neurobiol. 13 (2003) 50–56.

[17] S.B. Carroll, J.K. Grenier, S.D. Weatherbee, From DNA to Diversity.Molecular Genetics and the Evolution of Animal Design, BlackwellScience, Massachusetts, 2001.

[18] W.J. Gehring, Master Control Genes in Development and Evolution:The Homeobox Story, Yale University Press, London, 1998.

[19] A. Gonzalez, J.M. Lopez, O. Marın, Expression pattern of the home-obox proteinNkx2.1 in the developingXenopusforebrain, Brain Res.Gene Expr. Patterns 1 (2002) 181–185.

[20] A. Gonzalez, J.M. Lopez, C. Sanchez-Camacho, O. Marın, Regionalexpression of the homeobox geneNkx2.1 defines pallidal and in-terneuronal populations in the basal ganglia of amphibians, Neuro-science 114 (2002) 567–575.

[21] S. Guirado, J.C. Davila, M.A. Real, L. Medina, Light and electronmicroscopic evidence for projections from the thalamic nucleus ro-

, and000)

[ shlon-

[ iga,ein,n 29

[ f theergic2003)

[ ex’,

[ s of.

[ n ofla, J.

[ ap-fiedtratesurol.

[ a-998)

[ alies in

[ tivityn of

functional approach, Behav. Brain Sci. 26 (2003) 535–586.[2] I. Bachy, J. Berthon, S. Retaux, Defining pallial and subpallial co

partments in the developingXenopusforebrain, Mech. Dev. 11(2002) 163–172.

[3] I. Bachy, P. Vernier, S. Retaux, The LIM-homeodomain gene famin the developingXenopusbrain: conservation and divergences wthe mouse related to the evolution of the forebrain, J. Neurosc(2001) 7620–7629.

[4] K.M. Bishop, S. Garel, Y. Nakagawa, J.L.R. Rubenstein, DO’Leary, Emx1 andEmx2 cooperate to regulate cortical size, lamtion, neuronal differentiation, development of cortical efferents,thalamocortical pathfinding, J. Comp. Neurol. 457 (2003) 345–

[5] K.M. Bishop, G. Goudreau, D.D. O’Leary, Regulation of area idtity in mammalian neocortex byEmx2 andPax6, Science 288 (200344–349.

[6] M.R. Braford, Comparative aspects of forebrain organization inray-finned fishes: touchstones or not? Brain. Behav. E 46 (1259–274.

[7] A. Brox, Regionalizacion del Prosencefalo de la RanaXenopus laevis. Factores Moleculares Involucrados. Ph.D. Dissertation. Unsity of Murcia, Murcia, Spain, 2003.

[8] A. Brox, L. Puelles, B. Ferreiro, L. Medina, Expression of the geGAD67 and Distal-less-4 in the forebrain ofXenopus laeviscon-firms a common pattern in tetrapods, J. Comp. Neurol. 461 (2370–393.

[9] A. Brox, L. Puelles, B. Ferreiro, L. Medina, Expression of the geEmx1, Tbr1 andEomes(Tbr2) in the telencephalon ofXenopus laeviconfirms the existence of a ventral pallial division in tetrapodComp. Neurol. 474 (2004) 562–577.

10] S. Bulchand, E.A. Grove, F.D. Porter, S. Tole, LIM-homeodomgeneLhx2 regulates the formation of the cortical hem, Mech. D100 (2001) 165–175.

11] A. Bulfone, S. Martınez, V. Marigo, M. Campanella, A. Basile,Quaderi, C. Gattuso, J.L.R. Rubenstein, A. Ballabio, Expressiontern of theTbr2 (Eomesodermin) gene during mouse and chick brdevelopment, Mech. Dev. 84 (1999) 133–138.

tundus to targets in the basal ganglia, the dorsal ventricular ridgethe amygdaloid complex in a lizard, J. Comp. Neurol. 424 (2216–232.

22] G. Hauptmann, I. Soll, T. Gerster, The early embryonic zebrafiforebrain is subdivided into molecularly distinct transverse andgitudinal domains, Brain Res. Bull. 57 (2002) 371–375.

23] R.F. Hevner, L. Shi, N. Justice, Y. Hsueh, M. Sheng, S. SmA. Bulfone, A.M. Goffinet, A.T. Campagnoni, J.L.R. RubenstTbr1 regulates differentiation of the preplate and layer 6, Neuro(2001) 353–366.

24] J. Holzschuh, G. Hauptmann, W. Driever, Genetic analysis oroles of Hh, FGF8, and nodal signaling during Catecholaminsystem development in the zebrafish brain, J. Neurosci. 23 (5507–5519.

25] H.J. Karten, Homology and evolutionary origins of the ‘neocortBrain Behav. Evol. 38 (1991) 264–272.

26] H.J. Karten, J.L. Dubbeldam, The organization and projectionthe paleostriatal complex in the pigeon (Columba livia), J. CompNeurol. 148 (1973) 61–90.

27] J.E. LeDoux, C. Farb, D.A. Ruggiero, Topographic organizationeurons in the acoustic thalamus that project to the amygdaNeurosci. 10 (1990) 1043–1054.

28] R. Linke, A.D. De Lima, H. Schwegler, H.C. Pape, Direct syntic connections of axons from superior colliculus with identithalamo-amygdaloid projection neurons in the rat: possible subsof a subcortical visual pathway to the amygdala, J. Comp. Ne403 (1999) 158–170.

29] O. Marın, W.J.A.J. Smeets, A. Gonzalez, Basal ganglia organiztion in amphibians: chemoarchitecture, J. Comp. Neurol. 392 (1285–312.

30] O. Marın, W.J.A.J. Smeets, A. Gonzalez, Evolution of the basganglia in tetrapods: a new perspective based on recent studamphibians, Trends Neurosci. 21 (1998) 487–494.

31] L. Medina, A. Reiner, Neurotransmitter organization and connecof the basal ganglia in vertebrates: implications for the evolutiobasal ganglia, Brain Behav. Evol. 46 (1995) 235–258.

302 L. Medina et al. / Brain Research Bulletin 66 (2005) 297–302

[32] L. Medina, I. Legaz, G. Gonzalez, F. de Castro, J.L.R. Rubenstein,L. Puelles, Expression ofDbx1, Neurogenin2, Semaphorin5A, Cad-herin8, andEmx1 distinguish ventral and lateral pallial histogeneticdivisions in the developing mouse claustroamygdaloid complex, J.Comp. Neurol. 474 (2004) 504–523.

[33] N. Moreno, A. Gonzalez, Hodological characterization of the me-dial amygdala in anuran amphibians, J. Comp. Neurol. 466 (2003)389–408.

[34] N. Moreno, I. Bachy, S. Retaux, A. Gonzalez, LIM-homeodomaingenes as developmental and adult genetic markers ofXenopusfore-brain functional subdivisions, J. Comp. Neurol. 472 (2004) 52–72.

[35] Y. Murakami, M. Ogasawara, F. Sugahara, S. Hirano, N. Satoh, S.Kuratani, Identification and expression of the lampreyPax6 gene:evolutionary origin of the segmented brain of vertebrates, Develop-ment 128 (2001) 3521–3531.

[36] L. Muzio, B. DiBenedetto, A. Stoykova, E. Boncinelli, P. Gruss,A. Mallamaci, Conversion of cerebral cortex into basal ganglia inEmx2(−/−) Pax6(Sey/Sey) double-mutant mice, Nat. Neurosci. 5(2002) 737–745.

[37] T.J. Neary, The pallium of anuran amphibians, in: E.G. Jones, A.Peters (Eds.), Cerebral Cortex. Comparative Structure and Evolutionof Cerebral Cortex. Part I, vol. 8A, Plenum Press, New York, 1990,pp. 107–138.

[38] R.G. Northcutt, E. Kicliter, Organization of the amphibian telen-cephalon, in: S.O.E. Ebbesson (Ed.), Comparative Neurology of theTelencephalon, Plenum Press, New York, 1980, pp. 203–255.

[39] R.G. Northcutt, A. Reiner, H.J. Karten, Immunohistochemical studyof the telencephalon of the spiny dogfish,Squalus acanthias, J.Comp. Neurol. 277 (1988) 250–267.

[40] N. Papalopulu, C. Kintner,Xenopus Distal-lessrelated homeoboxgenes are expressed in the developing forebrain and are induced by

[ rainillary

[ m-997)

[ eycom-. 386

[ n-993)

[ on ofs. R.

[ oboxfore-

1993)

[ mains003)

[ a, J.riva-y the

[ tur-tex,.

[ asal

[51] A. Reiner, L. Medina, C.L. Veenman, Structural and functional evo-lution of the basal ganglia in vertebrates, Brain Res. Brain Res. Rev.28 (1998) 235–285.

[52] S. Retaux, M. Rogard, I. Bachy, V. Failli, M.J. Besson,Lhx9: a novelLIM-homeodomain gene expressed in the developing forebrain, J.Neurosci. 19 (1999) 783–793.

[53] F. Rodrıguez, J.C. Lopez, J.P. Vargas, Y. Gomez, C. Broglio, C.Salas, Conservation of spatial memory function in the pallial fore-brain of reptiles and ray-finned fishes, J. Neurosci. 22 (2002)2894–2903.

[54] K.B. Rohr, K.A. Barth, Z.M. Varga, S.W. Wilson, The nodal pathwayacts upstream of hedgehog signaling to specify ventral telencephalicidentity, Neuron 29 (2001) 341–351.

[55] F. Scalia, G. Gallousis, S. Roca, Differential projections of the mainand accessory olfactory bulb in the frog, J. Comp. Neurol. 305 (1991)443–461.

[56] K. Shimamura, D.J. Hartigan, S. Martınez, L. Puelles, J.L.R. Ruben-stein, Longitudinal organization of the anterior neural plate and neu-ral tube, Development 121 (1995) 3923–3933.

[57] A. Simeone, D. Acampora, M. Gulisano, A. Stornaiuolo, E.Boncinelli, Nested expression domains of four homeobox genes indeveloping rostral brain, Nature 358 (1992) 687–690.

[58] A. Simeone, M. Gulisano, D. Acampora, A. Stornaiuolo, M. Ram-baldi, E. Boncinelli, Two vertebrate homeobox gene related to theDrosophila empty spiraclesgene are expressed in the embryoniccerebral cortex, EMBO J. 11 (1992) 2541–2550.

[59] A. Smith-Fernandez, C. Pieau, J. Reperant, E. Boncinelli, M.Wassef, Expression of theEmx-1 andDlx-1 homeobox genes definethree molecularly distinct domains in the telencephalon of mouse,chick, turtle and frog embryos: implications for the evolution oftelencephalic subdivisions in amniotes, Development 125 (1998)

[ tern-996)

[ erosci.

[ rain

[culartrans-99)

[ l of

[ ce inomp.

[ ative

002)

[ f thes

rowth003)

[ -elen-

planar signals, Development 117 (1993) 961–975.41] M.A. Pombal, L. Puelles, Prosomeric map of the lamprey foreb

based on calretinin immunocytochemistry, Nissl stain, and ancmarkers, J. Comp. Neurol. 414 (1999) 391–422.

42] M.A. Pombal, A. El Manira, S. Grillner, Organization of the laprey striatum—transmitters and projections, Brain Res. 766 (1249–254.

43] M.A. Pombal, A. El Manira, S. Grillner, Afferents of the lamprstriatum with special reference to the dopaminergic system: abined tracing and immunohistochemical study, J. Comp. Neurol(1997) 71–91.

44] M. Price, Members ofDlx and Nkx2 gene families are regioally expressed in the developing forebrain, J. Neurobiol. 24 (11385–1399.

45] L. Puelles, Thoughts on the development, structure and evolutithe mammalian and avian telencephalic pallium, Philos. TranSoc. Lond. B Biol. Sci. 356 (2001) 1583–1598.

46] L. Puelles, J.L.R. Rubenstein, Expression patterns of homeand other putative regulatory genes in the embryonic mousebrain suggest a neuromeric organization, Trends Neurosci. 16 (472–479.

47] L. Puelles, J.L.R. Rubenstein, Forebrain gene expression doand the evolving prosomeric model, Trends Neurosci. 26 (2469–476.

48] L. Puelles, E. Kuwana, E. Puelles, A. Bulfone, K. ShimamurKeleher, S. Smiga, J.L.R. Rubenstein, Pallial and subpallial detives in the embryonic chick and mouse telencephalon, traced bexpression of the genesDlx-2, Emx-1, Nkx-2.1, Pax-6, andTbr-1, J.Comp. Neurol. 424 (2000) 409–438.

49] A. Reiner, Neurotransmitter organization and connections oftle cortex: implications for the evolution of mammalian isocorComp. Biochem. Physiol. Comp. Physiol. 104 (1993) 735–748

50] A. Reiner, S.E. Brauth, H.J. Karten, Evolution of the amniote bganglia, Trends Neurosci. 7 (1984) 320–325.

2099–2111.60] A. Stoykova, R. Fritsch, C. Walther, P. Gruss, Forebrain pat

ing defects in small eye mutant mice, Development 122 (13453–3465.

61] A. Stoykova, D. Teichel, M. Hallonet, P. Gruss,Pax6 modulates thdorsoventral patterning of the mammalian telencephalon, J. Neu20 (2000) 8042–8050.

62] G.F. Striedter, The telencephalon of tetrapods in evolution, BBehav. Evol. 49 (1997) 179–213.

63] L. Sussel, O. Marın, S. Kimura, J.L.R. Rubenstein, Loss ofNkx2.1homeobox gene function results in a ventral to dorsal molerespecification within the basal telencephalon: evidence for aformation of the pallidum into the striatum, Development 126 (193359–3370.

64] H. Toresson, S.S. Potter, K. Campbell, Genetic controdorsal–ventral identity in the telencephalon: opposing roles forPax6and Gsh2, Development 127 (2000) 4361–4371.

65] A. Vyas, B. Saha, E. Lai, S. Tole, Paleocortex is specified in miwhich dorsal telencephalic patterning is severely disrupted, J. CNeurol. 466 (2003) 545–553.

66] M.F. Wullimann, E. Rink, The teleostean forebrain: a comparand developmental view based on early proliferation,Pax6 activ-ity and catecholaminergic organization, Brain Res. Bull. 57 (2363–370.

67] K. Yun, S. Garel, S. Fischman, J.L.R. Rubenstein, Patterning olateral ganglionic eminence by theGsh1 andGsh2 homeobox generegulates striatal and olfactory bulb histogenesis and the gof axons through the basal ganglia, J. Comp. Neurol. 461 (2151–165.

68] K. Yun, S. Potter, J.L.R. Rubenstein,Gsh2 andPax6 play complementary roles in dorsoventral patterning of the mammalian tcephalon, Development 128 (2001) 193–205.