The vertebrate forebrain is formed at the rostral end of the neural plate under the regulation of local and specific signals emanating from both the endomesoderm and neuroectoderm. The development of the rostral and ventral forebrain in particular was difficult to study, mainly because no specific markers are available to date. Here, we report the identification of Vax1, a novel homeobox-containing gene identified in mouse, Xenopus and human. It is closely related to members of the Not and Emx gene families, all of which are required for the formation of structures where they are expressed. In mouse and Xenopus, Vax1 expression first occurs in the rostral neural plate, in the medial anterior neural ridge and adjacent ectoderm. Later, at midgestation in the mouse and tadpole stage in Xenopus, the expression remains confined in the derivatives of this territory which differentiate into rostromedial olfactory placode, optic nerve and disc, and anterior ventral forebrain. Together, these observations suggest that Vax1 could have an early evolutionary origin and could participate in the specification and formation of the rostral and ventral forebrain in vertebrates. Comparison of the limits of the expression territory of Vax1 with that of Dlx1, Pax6 and Emx1 indicates that the corticostriatal ridge is a complex structure with distinct identifiable genetic compartments. Besides, the study of Vax1 expression in Pax6-deficient homozygous brains indicates that its regulation is independent of Pax6, although the expression patterns of these two genes appear complementary in wild-type animals. Vax1 chromosomal location is mapped at the distal end of the mouse chromosome 19, linked with that of Emx2. These two genes may have arisen by tandem duplication. The Vax1 gene is thus an interesting new tool to study the rostral ventral forebrain patterning, morphogenesis and evolution as well as the terminal differentiation of the forebrain in mouse and Xenopus.

REFERENCES

REFERENCES
Acampora
D.
,
Mazan
S.
,
Lallemand
Y.
,
Avantaggiato
V.
,
Maury
M.
,
Simeone
A.
,
Brûlet
P.
(
1995
)
Forebrain and midbrain regions are deleted in Otx2 (/) mutants due to a defective anterior neuroectoderm specification during gastrulation.
Development
121
,
3279
3290
Anderson
S. A.
,
Eisenstat
D. D.
,
Shi
L.
,
Rubenstein
J. L. R.
(
1997
)
Interneuron migration from the basal forebrain to neocortex: dependence on Dlx genes.
Science
278
,
474
476
Anderson
S. A.
,
Mengshen
Q.
,
Bulfone
A.
,
Eisenstat
D. D.
,
Meneses
J.
,
Pedersen
R.
,
Rubenstein
J. L. R.
(
1997
)
Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons.
Neuron
19
,
27
37
Ang
S. L.
,
Conlon
R. A.
,
Jin
O.
,
Rossant
J.
(
1994
)
Positive and negative signals from mesoderm regulate the expression of mouse Otx 2 in ectoderm explants.
Development
120
,
2979
2989
Ang
S. L.
,
Jin
O.
,
Rhinn
M.
,
Daigle
N.
,
Stevenson
L.
,
Rossant
J.
(
1996
)
A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain.
Development
122
,
243
252
Ang
S. L.
,
Rossant
J.
(
1993
)
Anterior mesendoderm induces mouse Engrailed genes in explant cultures.
Development
118
,
139
149
Bayer
S. A.
,
Altman
J.
(
1987
)
Development of the preoptic area: Time and site of origin, migratory routes, and settling patterns of its neurons.
J. Comp. Neurol
265
,
65
95
Bayer
S. A.
,
Altman
J.
(
1987
)
Directions in neurogenic gradients and pattern of anatomical connections in the telencephalon.
Prog. Neurobiol
29
,
57
106
Bayer
S. A.
,
Altman
J.
(
1991
)
Development of the endopiriform nucleus and the claustrum in the rat brain.
Neuroscience
45
,
391
412
Boek
R.
,
Kolakofsky
D.
(
1994
)
Position +5 and +6 can be major determinants of the efficiency of non-AUG initiation codons for protein synthesis.
EMBO J
13
,
3608
3617
Boulder Commitee
(
1970
)
Embryonic Vertebrate Central System: Revised Terminology.
Anat. Rec
166
,
257
262
Bouwmeester
T.
,
Kim
S.-H.
,
Sasai
Y.
,
Lu
B.
,
De Robertis
E.
(
1996
)
Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann's organizer.
Nature
382
,
595
601
Brunelli
S.
,
Faiella
A.
,
Capra
V.
,
Nigro
V.
,
Simeone
A.
,
Cama
A.
,
Boncinelli
E.
(
1996
)
Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly.
Nat. Genet
12
,
94
6
Bulfone
A.
,
Puelles
L.
,
Porteus
M. H.
,
Frohman
M. A.
,
Martin
G. R.
,
Rubenstein
J. L. R.
(
1993
).
Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12.5 mouse forebrain defines potential transverse and longitudinal segmental boundaries.
J. Neurosci
13
,
3155
3172
Caric
D.
,
Gooday
D.
,
Hill
R. E.
,
McConnell
S. K.
,
Price
D. J.
(
1997
)
Determination of the migratory capacity of embryonic cortical cells lacking the transcription factor Pax-6.
Development
124
,
5087
5096
Cavener
D. R.
,
Ray
S. C.
(
1991
)
Eukaryotic start and stop translation sites.
Nucl. Acids Res
19
,
3185
3192
Copeland
N. G.
,
Jenkins
A. G.
(
1991
)
Development and applications of a molecular genetic linkage map of the mouse genome.
Trends Genet
7
,
113
118
Couly
G. F.
,
Le Douarin
N. M.
(
1987
)
Mapping of the early neural primordium in quail-chick chimeras. II. The prosencephalic neural plate and neural folds: implications for the genesis of cephalic human congenital abnormalities.
Dev. Biol
120
,
198
214
Dale
J. K.
,
Vesque
C.
,
Lints
T. J.
,
Sampath
T. K.
,
Furley
A.
,
Dodd
J.
,
Placzek
M.
(
1997
)
Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm.
Cell
90
,
257
269
Dalton
D.
,
Chadwick
R.
,
McGinnis
W.
(
1989
)
Expression and embryonic function of empty spiracles: a Drosophila homeobox gene withtwo patterning functions on the anterior-posterior axis of the embryo.
Genes Dev
3
,
1940
1956
De Carlos
J. A.
,
Lopez-Mascaraque
L.
,
Valverde
F.
(
1995
)
The telencephalic vesicles are innervated by olfactory placode-derived cells: a possible mechanism to induce neocortical development.
Neuroscience
68
,
1167
1178
De Carlos
J. A.
,
Lopez-Mascaraque
L.
,
Valverde
F.
(
1996
)
Dynamics of cell migration from the lateral ganglionic eminence in the rat.
J. Neurosci
16
,
6146
6156
Doniach
T.
(
1993
)
Planar and vertical induction of anteroposterior pattern during the development of the amphibian central nervous system.
J. Neurobiol
24
,
1256
1275
Eagleson
G.
,
Ferreiro
B.
,
Harris
W. A.
(
1995
)
Fate of the anterior neural ridge and the morphogenesis of the Xenopus forebrain.
J. Neurobiol
28
,
146
158
Eagleson
G. W.
,
Harris
W. A.
(
1990
)
Mapping of the presumptive brain regions in the neural plate of Xenopus laevis.
J. Neurobiol
21
,
427
440
Ericson
J.
,
Morton
S.
,
Kawakami
A.
,
Roelink
H.
,
Jessell
T. M.
(
1996
)
Two critical periods of sonic hedgehog signaling required for the specification of motoneuron identity.
Cell
87
,
661
673
Fentress
J. C.
,
Stanfield
B. B.
,
Cowan
W. M.
(
1981
)
Observations on the development of the striatum in mice and rats.
Anat. Embryol
163
,
275
298
Finkelstein
R.
,
Boncinelli
E.
(
1994
)
From fly head to mammalian forebrain: the story of otd and Otx.
Trends Genet
10
,
310
315
Fishell
G.
(
1997
)
Regionalization in the mammalian telensephalon.
Curr. Opin. Neurobiol
7
,
62
69
Gans
C.
(
1989
)
Stages in the origin of vertebrates: analysis by means of scenarios.
Biol. Rev. Camb. Philos. Soc
64
,
221
268
Glinka
A.
,
Wei
W.
,
Onichtchouk
D.
,
Blumenstock
C.
,
Niehrs
C.
(
1997
)
Head induction by simultaneous repression of Bmp and Wnt signalling in Xenopus.
Nature
389
,
517
519
Halliday
A. L.
,
Cepko
C. L.
(
1992
)
Generation and migration of cells in the developing striatum.
Neuron
9
,
15
26
Harland
R. M.
(
1991
)
In situ hybridization: an improved whole-mount method for Xenopus embryos.
Methods Cell Biol
36
,
685
695
Hirth
F.
,
Therianos
S.
,
Loop
T.
,
Gehring
W. J.
,
Reichert
H.
,
Furukubo-Tokunaga
K.
(
1995
)
Developmental defects in brain segmentation caused by mutations of the homeobox genes orthodenticle and empty spiracles in Drosophila.
Neuron
15
,
769
778
Hogan
B. L. M.
,
Horsburgh
G.
,
Cohen
J.
,
Hetherington
C. M.
,
Fisher
G.
,
Lyon
M. F.
(
1986
)
Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse.
J. Embryol. exp. Morph
97
,
95
110
Hollemann
T.
,
Bellefroid
E.
,
Pieler
T.
(
1998
)
The Xenopus homologue of the Drosophila gene tailless has a function in early eye development.
Development
125
,
2425
2432
Houart
C.
,
Westerfield
M.
,
Wilson
S. W.
(
1998
)
A small population of anterior cells patterns the forebrain during zebrafish gastrulation.
Nature
391
,
788
792
Israel
D. I.
(
1993
)
A PCR-based method for high stringency screening of DNA libraries.
Nucleic Acid Res
21
,
2627
2631
Juan
T. S.-C.
,
McNiece
I. K.
,
Argento
J. M.
,
Jenkins
N. A.
,
Gilbert
D. J.
,
Copland
N. G.
(
1997
)
Identification and mapping of Casp7, a cystein protease resembling CPP32beta, interleukin-1beta converting enzyme, and CED-3.
Genomics
40
,
86
93
Kastury
K.
,
Druck
T.
,
Huebner
K.
,
Barletta
C.
,
Acampora
D.
,
Simeone
A.
,
Faiella
A.
,
Boncinelli
E.
(
1994
)
Chromosome locations of human EMX and OTX genes.
Genomics
22
,
41
45
Kozak
M.
(
1986
)
Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes.
Cell
44
,
283
292
Krumlauf
R.
,
Marshall
H.
,
Studer
M.
,
Nonchev
S.
,
Sham
M. H.
,
Lumsden
A.
(
1994
)
Hox homeobox genes and regionalisation of the nervous system.
J. Neurobiol
24
,
1328
1340
Lufkin
T.
(
1996
)
Transcriptional control of Hox genes in vertebrate nervous system.
Curr. Opin. Genet. Dev
6
,
575
580
Lumsden
A.
,
Krumlauf
R.
(
1996
)
Patterning the vertebrate neuraxis.
Science
274
,
1109
1115
Mastick
G. S.
,
Davis
N. M.
,
Andrews
G. L.
,
Easter
S. S.
Jr
(
1997
)
Pax-6 functions in boundary formation and axon guidance in the embryonic mouse forebrain.
Development
124
,
1985
1997
Matsuo
I.
,
Kuratani
S.
,
Kimura
C.
,
Takeda
N.
,
Aizawa
S.
(
1995
)
Mouse Otx 2 functions in the formation and patterning of rostral head.
Genes Dev
9
,
2646
2658
Matsuo
T.
,
Osumi-Yamashita
N.
,
Noji
S.
,
Ohuchi
H.
,
Koyama
E.
,
Myokai
F.
,
Matsuo
N.
,
Taniguchi
S.
,
Doi
H.
,
Ninomiya
Y.
,
Fujiwara
M.
,
Watanabe
T.
,
Eto
K.
(
1993
)
A mutation in the Pax-6 gene in rat small eye is associated with impaired migration of midbrain crest cells.
Nature Genet
3
,
299
304
Oliver
G.
,
Mailhos
A.
,
Wehr
R.
,
Copeland
N. G.
,
Jenkins
N. A.
,
Gruss
P.
(
1995
)
Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development.
Development
121
,
4045
55
Pannese
M.
,
Polo
C.
,
Andreazzoli
M.
,
Vignali
R.
,
Kablar
B.
,
Barsacchi
G.
,
Boncinelli
E.
(
1995
)
The Xenopus homologue of Otx 2 is a maternal homeobox gene that demarcates and specifies anterior body regions.
Development
121
,
707
720
Pellegrini
M.
,
Mansouri
A.
,
Simeone
A.
,
Boncinelli
E.
,
Gruss
P.
(
1996
)
Dentate gyrus formation requires Emx2.
Development
122
,
3893
3898
Pellier
V.
,
Astic
L.
(
1994
)
Histochemical and immunocytochemical study of the migration of neurons from the rat olfactory placode.
Cell Tissue Research
275
,
587
598
Price
M.
,
Lemaistre
M.
,
Pischetola
M.
,
Di Lauro
R.
,
Duboule
D.
(
1991
)
A mouse gene related to Distal-less shows a restricted expression in the developing forebrain.
Nature
351
,
748
751
Puelles
L.
,
Rubenstein
J. L. R.
(
1993
)
Expression patterns of homeobox and other putative regulatory genes in the embryonic mouse forebrain suggests a neuromeric organization.
Trends Neurosci
16
,
472
479
Qiu
M.
,
Anderson
S.
,
Chen
S.
,
Meneses
J. J.
,
Hevner
R.
,
Kuwana
E.
,
Pedersen
R. A.
,
Rubenstein
J. L. R.
(
1996
)
Mutation of the Emx-1 homeobox gene disruptd the corpus callosum.
Dev. Biol
178
,
174
178
Roberts
R. C.
(
1967
)
Small-eyes, a new dominant mutant in the mouse.
Genet. Res
9
,
121
122
Ruiz i Altaba
A.
(
1994
)
Pattern formation in the vertebrate neural plate.
Trends Neurosci
17
,
233
243
Saha
M. S.
,
Grainger
R. M.
(
1992
)
A labile period in the determination of the anterior-posterior axis during early neural development in Xenopus.
Neuron
8
,
1003
1014
Schwanzel-Fukuda
M.
,
Crossin
K. L.
,
Pfaff
D. W.
,
Bouloux
P. M. G.
,
Hardelin
J. P.
,
Petit
C.
(
1996
)
Migration of luteinizing hormone-releasing hormone (LHRH) neurons in early human embryos.
J. Comp. Neurol
366
,
547
557
Shawlot
W.
,
Behringer
R. R.
(
1995
)
Requirement for Lim1 in head-organizer function.
Nature
374
,
425
430
Shimamura
K.
,
Rubinstein
J. L. R.
(
1997
)
Inductive interactions direct early regionalization of the mouse forebrain.
Development
124
,
2709
2718
Simeone
A.
,
Acampora
D.
,
Gulisano
M.
,
Stornaiuolo
A.
,
Boncinelli
E.
(
1992
)
Nested expression domains of four homeobox genes in developing rostral brain.
Nature
358
,
687
690
Simeone
A.
,
Acampora
D.
,
Mallamaci
A.
,
Stornaiuolo
A.
,
D'Apice
M. R.
,
Nigro
V.
,
Boncinelli
E.
(
1993
)
A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo.
EMBO J
12
,
2735
2747
Simeone
A.
,
Gulisano
M.
,
Acampora
D.
,
Stornaiuolo
A.
,
Rambaldi
M.
,
Boncinelli
E.
(
1992
)
Two vertebrate homeobox genes related to the Drosophilaempty spiracles gene are expressed in the embryonic cerebral cortex.
EMBO J
11
,
2541
2550
St-Onge
L.
,
Sosa-Pineda
B.
,
Chowdhury
K.
,
Mansouri
A.
,
Gruss
P.
(
1997
)
Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas.
Nature
387
,
406
409
Stein
S.
,
Kessel
M.
(
1995
)
A homeobox gene involved in node, notochord and neural plate formation of chick embryos.
Mech. Dev
49
,
37
48
Stein
S.
,
Niss
K.
,
Kessel
M.
(
1996
)
Differential activation of the clustered homeobox genes CNOT2 and CNOT1 during notogenesis in the chick.
Dev. Biol
180
,
519
533
Stoykova
A.
,
Fritsch
R.
,
Walther
C.
,
Gruss
P.
(
1996
)
Forebrain patterning defects in Small eye mutant mice.
Development
122
,
3453
3465
Stoykova
A.
,
Götz
M.
,
Gruss
P.
,
Price
J.
(
1997
)
Pax6 -dependent regulation of adhesive patterning, R-cadherin expression and boundary formation in developing forebrain.
Development
124
,
3765
3777
Stoykova
A.
,
Gruss
P.
(
1994
)
Roles of Pax -genes in developing and adult brain as suggested by expression patterns.
J. Neurosci
14
,
1395
1412
Szele
F. G.
,
Cepko
C. L.
(
1996
)
A subset of clones in the chick telencephalon arranged in rostrocaudal arrays.
Current Biol
6
,
1685
1690
Talbot
W. S.
,
Trevarrow
B.
,
Halpern
M. E.
,
Melby
A. E.
,
Farr
G.
,
Postlethwait
J. H.
,
Jowett
T.
,
Kimmel
C. B.
,
Kimelman
D.
(
1995
)
A homeobox gene essential for zebrafish notochord development.
Nature
378
,
150
157
Thomas
P.
,
Beddington
R.
(
1996
)
Anterior primitive endoderm may be responsible for patterning the anterior neural plate of the mouse embryo.
Current Biol
6
,
1487
1496
Thor
T.
(
1995
)
The genetics of brain development: Conserved programs in flies and mice.
Neuron
15
,
975
977
von Dassow
G.
,
Schmidt
J. E.
,
Kimelman
D.
(
1993
)
Induction of the Xenopus organizer: expression and regulation of Xnot, a novel FGF and activin-regulated homeo box gene.
Genes Dev
7
,
355
366
Walldorf
U.
,
Gehring
W. J.
(
1992
)
Empty spiracles, a gap gene containing a homeobox involved in Drosophila head development.
EMBO J
11
,
2247
2259
Walther
C.
,
Gruss
P.
(
1991
)
Pax-6, a murine paired box gene, is expressed in the developing CNS.
Development
113
,
1435
1449
Warren
N.
,
Price
D. J.
(
1997
)
Roles of Pax-6 in murine diencephalic development.
Development
124
,
1573
1582
Wijnholds
J.
,
Chowdhury
K.
,
Wehr
R.
,
Gruss
P.
(
1995
)
Segment specific expression of the neuronatin gene during early hindbrain development.
Dev. Biol
171
,
73
84
Yoshida
M.
,
Suda
Y.
,
Matsuo
I.
,
Miyamoto
N.
,
Takeda
N.
,
Kuratani
S.
,
Aizawa
S.
(
1997
)
Emx1 and Emx2 functions in development of dorsal telencephalon.
Development
124
,
101
111
Zheng
L. M.
,
Pfaff
D. W.
,
Schwanzel-Fukuda
M.
(
1992
)
Electron microscopic identification of luteinizing hormone-releasing hormone-immunoreactive neurons in the medial olfactory placode and basal forebrain of embryonic mice.
Neuroscience
46
,
407
418
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