Mouse Otx2 is a bicoid-class homeobox gene, related to the Drosophila orthodenticle (otd) gene. Expression of this gene is initially widespread in the epiblast at embryonic day 5.5 but becomes progressively restricted to the anterior end of the embryo at the headfold stage. In flies, loss of function mutations in otd result in deletion of pre-antennal and antennal segments; which leads to the absence of head structures derived from these segments. To study the function of Otx2 in mice, we have generated a homeobox deletion mutation in this gene. Mice homozygous for this mutation show severe defects in gastrulation and in formation of axial mesoderm and loss of anterior neural tissues. These results demonstrate that Otx2 is required for proper development of the epiblast and patterning of the anterior brain in mice, and supports the idea of evolutionary conservation of the function of Otd/Otx genes in head development in flies and mice.

Reference

Ang
S.-L.
,
Rossant
J.
(
1993
)
Anterior mesendoderm induces mouse Engrailed genes in explant cultures.
Development
118
,
139
149
Ang
S.-L.
,
Rossant
J.
(
1994
)
HNF-3 is essential for node and notochord formation in mouse development.
Cell
78
,
561
574
Ang
S.-L.
,
Wierda
A.
,
Wong
D.
,
Stevens
K. A.
,
Cascio
S.
,
Rossant
J.
,
Zaret
K. S.
(
1993
)
The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF-3/ forkhead proteins.
Development
119
,
1301
1315
Ang
S.-L.
,
Conlon
R. A.
,
Jin
O.
,
Rossant
J.
(
1994
)
Positive and negative signals from mesoderm regulate the expression of mouse Otx2 in ectoderm explants.
Development
120
,
979
989
Bailly-Cuif
L.
,
Gulisano
M.
,
Broccoli
V.
,
Boncinelli
E.
(
1995
)
c-otx2 is expressed in two different phases of gastrulation and is sensitive to retinoic acid treatment in chick embryo.
Mech. Dev
49
,
49
63
Barnes
,
Joseph
D.
,
Crosby
J. L.
,
Jones
C. M.
,
Wright
C. V. E.
,
Hogan
B. L. M.
(
1994
)
Embryonic expression of Lim-1, the mouse homolog of Xenopus XLim-1, suggests a role in lateral mesoderm differentiation and neurogenesis.
Dev. Biol
161
,
168
178
Beddington
R. S. P.
(
1994
)
Induction of a second neural axis by the mouse node.
Development
120
,
613
620
Blitz
I. C.
,
Cho
K. W. Y.
(
1995
)
Anterior neurectoderm is progressively induced during gastrulation: the role of the Xenopus homeobox gene orthodenticle.
Development
121
,
993
1004
Blum
M.
,
Gaunt
S. J.
,
Cho
K. W. Y.
,
Steinbeisser
H.
,
Blumberg
B.
,
Bittner
D.
,
De Robertis
E. M.
(
1992
)
Gastrulation in the mouse: the role of the homeobox gene goosecoid.
Cell
69
,
1097
1106
Candia
A. H.
,
Hu
J.
,
Crosby
J.
,
Lalley
P. A.
,
Noden
D.
,
Nadeau
J. H.
,
Wright
C. V. E.
(
1992
)
Mox-1 and Mox-2 define a novel homeobox gene subfamily and are differentially expressed during early mesodermal patterning in mouse embryos.
Development
116
,
1123
1136
Dalton
D.
,
Chadwick
R.
,
McGinnis
W.
(
1989
)
Expression and embryonic function of empty spiracles: a Drosophila homeobox gene with two patterning functions on the anterior-posterior axis of the embryo.
Genes Dev
3
,
1940
1956
Davis
C. A.
,
Holmyard
D. P.
,
Millen
K. J.
,
Joyner
A. L.
(
1991
)
Examining pattern formation in mouse, chicken and frog embryos with an En -specific antiserum.
Development
111
,
287
298
Dietrich
S.
,
Schubert
F. R.
,
Gruss
P.
(
1993
)
Altered Pax gene expression in murine notochord mutants: the notochord is required to initiate and maintain ventral identity in the somite.
Mech. Dev
44
,
189
207
Doniach
T.
(
1993
)
Planar and vertical induction of anteroposterior pattern during the development of the amphibian central nervous system.
J. Neurobiol
24
,
1256
1275
Finkelstein
R.
,
Smouse
D.
,
Theresa
M. C.
,
Spradling
A. C.
,
Perrimon
N.
(
1990
)
The orthodenticle gene encodes a novel homeo domain protein involved in the development of the Drosophila nervous system and ocellar visual structures.
Genes Dev
4
,
1516
1527
Finkelstein
R.
,
Boncinelli
E.
(
1994
)
From fly to mammalian forebrain: the story of otd and Otx.
Trends Neurosci
9
,
310
315
Guillemot
F.
,
Joyner
A. L.
(
1993
)
Dynamic expression of the murine achaete-scute homolog (MASH-1) in the developing nervous system.
Mech. Dev
42
,
171
185
Herrmann
B. G.
(
1991
)
Expression pattern of the Brachyury gene in whole-mount mutant embryos.
Development
113
,
913
917
Krumlauf
R.
(
1994
)
Hox genes in vertebrate development.
Cell
78
,
191
201
Lawrence
P. A.
,
Morata
G.
(
1994
)
Homeobox genes: Their function in Drosophila segmentation and pattern formation.
Cell
78
,
181
189
Lawson
K. A.
,
Meneses
J. J.
,
Pedersen
R. A.
(
1991
)
Clonal analysis of epiblast fate during germ layer formation in the mouse embryo.
Development
113
,
891
911
Monaghan
A. P.
,
Kaestner
K. H.
,
Grau
E.
,
Schutz
G.
(
1993
)
Postimplantation expression patterns indicate a role for the mouse forkhead /HNF-3, andgenes in determination of the definitive endoderm, chordamesoderm and neurectoderm.
Development
119
,
567
578
Nagy
A.
,
Rossant
J.
,
Nagy
R.
,
Abramow-Newerly
W.
,
Roeder
J. C.
(
1993
)
Viable cell culture-derived mice from early passage embryonic stem cells.
Proc. Natl. Acad. Sci. USA
90
,
8424
8428
Pannese
M.
,
Polo
C.
,
Andreazzoli
M.
,
Vignali
R.
,
Kablar
B.
,
Barsacchi
G.
,
Boncinelli
E.
(
1995
)
The Xenopus homologue of Otx2 is a maternal homeobox gene that demarcates and specifies anterior body regions.
Development
121
,
707
720
Rong
P. M.
,
Teillet
M.-A.
,
Ziller
C.
,
Le Douarin
N. M.
(
1992
)
The neural tube/notochord complex is necessary for vertebral but not limb and body wall striated muscle differentiation.
Development
115
,
657
672
Sasaki
H.
,
Hogan
B. l. M.
(
1993
)
Differential expression of multiple fork head related genes during gastrulation and axial pattern in the mouse embryo.
Development
118
,
47
59
Serafini
T.
,
Kennedy
T.
,
Galko
N.
,
Mirzayan
C.
,
Jessell
T.
,
Tessier-Lavigne
M.
(
1994
)
The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegansUNC-6.
Cell
78
,
409
424
Shawlot
W.
,
Behringer
R. M.
(
1995
)
Requirement for Lim1 in head-organizer function.
Nature
374
,
425
430
Simeone
A.
,
Acampora
D.
,
Gulisano
M.
,
Stornaiuolo
A.
,
Boncinelli
E.
(
1992
)
Nested expression domains of four homeobox genes in developing brain.
Nature
358
,
687
690
Simeone
A.
,
Gulisano
M.
,
Acampora
D.
,
Stornaiuolo
A.
,
Rambaldi
M.
,
Boncinelli
E.
(
1992
)
Two vertebrate homeobox genes related to the Drosophila empty spiracles gene are expressed in the embryonic cerebral cortex.
EMBO J
11
,
2541
2550
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.
,
Avantaggiato
V.
,
Moroni
M. C.
,
Mavillo
F.
,
Arra
C.
,
Cotelli
R.
,
Nigro
V.
,
Acampora
D.
(
1995
)
Retinoic acid induces stage-specific antero-posterior transformation of rostral central nervous system.
Mech. Dev
51
,
83
98
Slack
J.
,
Tannahill
D.
(
1992
)
Mechanism of anteroposterior axis specification in vertebrates. Lessons from amphibians.
Development
114
,
285
302
Tam
P. P. L.
(
1989
)
Regionalization of the mouse embryonic ectoderm: allocation of prospective ectodermal tissues during gastrulation.
Development
107
,
55
67
Tao
W.
,
Lai
E.
(
1992
)
Telencephalon restricted expression fo BF-1, a new member of the HNF-3/ forkhead gene family, in the developing rat brain.
Neuron
8
,
957
966
Teillet
M.-A.
,
Le Douarin
N. M.
(
1983
)
Consequences of neural tube and notochord excision on the development of the peripheral nervous system in the chick embryo.
Dev. Biol
98
,
192
211
Tybulewicz
V. L. J.
,
Crawford
C. E.
,
Jackson
P. K.
,
Bronson
R. T.
,
Mulligan
R. C.
(
1991
)
Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene.
Cell
65
,
1153
1163
Waddington
C. H.
(
1933
)
Induction by the primitive streak and its derivatives in the chick.
J. Exp. Biol
10
,
38
46
Weinstein
D. C.
,
Ruiz i Altaba
A.
,
Chen
W. S.
,
Hoodless
P.
,
Prezioso
V. R.
,
Jessell
T. M.
,
Darnell
J. E.
Jr
(
1994
)
The winged-helix transcription factor HNF-3 is required for notochord development in the mouse embryo.
Cell
78
,
575
588
Wilkinson
D. G.
,
Bhatt
S.
,
Cook
M.
,
Boncinelli
E.
,
Krumlauf
R.
(
1989
)
Segmental expression of Hox-2 homeobox genes in the developing mouse hindbrain.
Nature
341
,
405
409
Wilkinson
D. G.
,
Bhatt
S.
,
Chavrier
P.
,
Bravo
R.
,
Charnay
P.
(
1989
)
Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse.
Nature
337
,
461
464
Yamaguchi
T. P.
,
Dumont
D. J.
,
Conlon
R. A.
,
Breitman
M. L.
,
Rossant
J.
(
1993
)
flk-1, an flt -related receptor kinase is an early marker for endothelial cell precursors.
Development
118
,
489
498
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