Despite the obvious differences in anatomy between invertebrate and vertebrate brains, several genes involved in the development of both brain types belong to the same family and share similarities in expression patterns. Drosophila orthodenticle (otd) and murine Otx genes exemplify this, both in terms of expression patterns and mutant phenotypes. In contrast, sequence comparison of OTD and OTX gene products indicates that homology is restricted to the homeodomain suggesting that protein divergence outside the homeodomain might account for functional differences acquired during brain evolution. In order to gain insight into this possibility, we replaced the murine Otx1 gene with a Drosophila otd cDNA. Strikingly, epilepsy and corticogenesis defects due to the absence of Otx1 were fully rescued in homozygous otd mice. A partial rescue was also observed for the impairments of mesencephalon, eye and lachrymal gland. In contrast, defects of the inner ear were not improved suggesting a vertebrate Otx1-specific function involved in morphogenesis of this structure. Furthermore, otd, like Otx1, was able to cooperate genetically with Otx2 in brain patterning, although with reduced efficiency. These data favour an extended functional conservation between Drosophila otd and murine Otx1 genes and support the idea that conserved genetic functions required in mammalian brain development evolved in a primitive ancestor of both flies and mice.

REFERENCES

Acampora
D.
,
Mazan
S.
,
Lallemand
Y.
,
Avantaggiato
V.
,
Maury
M.
,
Simeone
S.
,
Brulet
P.
(
1995
)
Forebrain and midbrain regions are deleted Otx2/ mutants due to a defective anterior neuroectoderm specifiction during gastrulation.
Development
121
,
3279
3290
Acampora
D.
,
Mazan
S.
,
Avantaggiato
V.
,
Barone
P.
,
Tuorto
F.
,
Lallemand
Y.
,
Brûlet
P. A.
,
Simeone
A.
(
1996
)
Epilepsy and brain abnormalities in mice lacking the Otx1 mice.
Nature Gen
14
,
218
222
Acampora
D.
,
Avantaggiato
V.
,
Tuorto
F.
,
Simeone
A.
(
1997
)
Genetic control of brain morphogenesis through Otx gene dosage requirement.
Development
124
,
3639
3650
Bachiller
D.
,
Macias
A.
,
Duboule
D.
,
Morata
G.
(
1994
)
Conservation of a functional hierarchy between mammalian and insect Hox/HOM genes.
EMBO J
13
,
1930
1941
Bally-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
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
Callaerts
P.
,
Halder
G.
,
Gehring
W. J.
(
1997
)
Pax-6 in development and evolution.
Annu. Rev. Neurosci
20
,
483
532
Cohen
S. M.
,
Jurgens
G.
(
1991
)
Drosophila headlines.
Trends Genet
7
,
267
272
Crossley
P. H.
,
Martin
G. R.
(
1995
)
The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryos.
Development
121
,
439
451
Crossley
P. H.
,
Martinez
S.
,
Martin
G. R.
(
1996
)
Midbrain development induced by FGF8 in the chick embryo.
Nature
380
,
66
68
Duboule
D.
,
Dolle
P.
(
1989
)
The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes.
EMBO J
8
,
1497
1505
Finkelstein
R.
,
Perrimon
N.
(
1990
)
The orthodenticle gene is regulated by bicoid and torso and specifies Drosophila head development.
Nature
346
,
485
488
Finkelstein
R.
,
Smouse
D.
,
Capaci
T. M.
,
Spradling
A. C.
,
Perrimon
N.
(
1990
)
The orthodenticle gene encodes a novel homeodmain protein involved in the development the Drosophila nervous system and ocellar visual structures.
Genes Dev
4
,
1516
1527
Finkelstein
R.
,
Boncinelli
E.
(
1994
)
From fly head to mammalian forebrain: the story of otd and Otx.
Trends Genet
10
,
310
315
Frantz
G. D.
,
Weimann
J. M.
,
Levin
M. E.
,
McConnell
S. K.
(
1994
)
Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum.
J. Neurosci
14
,
5725
5740
Gans
C.
,
Northcutt
R. G.
(
1983
)
Neural crest and the origin of vertebrates: A new head.
Science
220
,
268
274
Gavrieli
Y.
,
Sherman
Y.
,
Ben-Sasson
S. A.
(
1992
)
Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.
J. Cell Biol
119
,
493
501
Graham
A.
,
Papalopulu
N.
,
Krumlauf
M.
(
1989
)
The murine and Drosophila homeobox clusters have common features of organization and expression.
Cell
57
,
367
378
Haddon
C. M.
,
Lewis
J. H.
(
1991
)
Hyaluronan as a propellant for epithelial movement: the development of semiciruclar canals in the inner ear of Xenopus.
Development
112
,
541
550
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 gene orthodenticle and empy spiracles in Drosophila.
Neuron
15
,
1
20
Holland
P.
,
Ingham
P.
,
Krauss
S.
(
1992
)
Mice and flies head to head.
Nature
358
,
627
628
Joyner
A. L.
(
1996
)
Engrailed, Wnt and Pax genes regulate midbrain-hindbrain development.
Trends Genet
12
,
15
20
Krumlauf
R.
(
1994
)
Hox genes in vertebrate development.
Cell
78
,
191
201
Leuzinger
S.
,
Hirth
F.
,
Gehrlich
D.
,
Acampora
D.
,
Simeone
A.
,
Gehring
W. J.
,
Finkelstein
R.
,
Furukubo-Tokunaga
K.
,
Reichert
H.
(
1998
)
Functional equivalence of the fly orthodenticle gene and the human OTX genes in embryonic brain development of Drosophila.
Development
125
,
1703
1710
Lewis
E. B.
(
1978
)
A gene complex controlling segmentation in Drosophila.
Nature
276
,
565
570
Matsuo
I.
,
Kuratani
S.
,
Kimura
C.
,
Takeda
N.
,
Aizawa
S.
(
1995
)
Mouse Otx2 functions in the formation and patterning of rostral head.
Genes Dev
9
,
2646
2658
McGinnis
W.
,
Krumlauf
R.
(
1992
)
Homeobox genes and axial patterning.
Cell
68
,
283
302
McMahon
A. P.
,
Joyner
A. L.
,
Bradley
A.
,
McMahon
J. A.
(
1992
).
The midbrain-hindbrain phenotype of Wnt-1/Wnt-1 mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum.
Cell
69
,
581
595
Mercier
P.
,
Simeone
A.
,
Cotelli
F.
,
Boncinelli
E.
(
1995
)
Expression pattern of two Otx genes suggests a role in specifying anterior body structures in zebrafish.
Int. J. Dev. Biol
39
,
559
573
Pannese
M.
,
Polo
C.
,
Abdreazzoli
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 structures in frog embryos.
Development
121
,
707
720
Reichert
H.
,
Boyan
G.
(
1997
)
Building a brain: developmental insights in insects.
Trends Neurosci
20
,
258
264
Royet
J.
,
Finkelstein
R.
(
1995
)
Pattern formation in Drosophila head development: the role of the orthodenticle homeobox gene.
Development
121
,
3561
3572
Rubenstein
J. L. R.
,
Martinez
S.
,
Shimamura
K.
,
Puelles
L.
(
1994
)
The embryonic vertebrate forebrain: the prosomeric model.
Science
266
,
578
580
Schmidt-Ott
U.
,
Gonzales-Gaitan
M.
,
Jäckle
H.
,
Technau
G. M.
(
1994
)
Number, identity, and sequence of the Drosophila head segments as revealed by neural elements and their deletion patterns in mutants.
Proc. Natl. Acad. Sci. USA
91
,
8363
8367
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
Thor
S.
(
1995
)
The genetics of brain development: conserved programs in flies and mice.
Neuron
15
,
975
977
van der Hoeven
F.
,
Zakany
J.
,
Duboule
D.
(
1996
)
Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls.
Cell
85
,
1025
1035
Wada
S.
,
Katsuyama
Y.
,
Sato
Y.
,
Itoh
C.
,
Saiga
H.
(
1996
)
Hroth an orthodenticle-related homeobox gene of the ascidian, Halocynthia roretzi: its expression and putative roles in the axis formation during embryogenesis.
Mech. Dev
60
,
59
71
Wassarman
K. M.
,
Lewandoski
M.
,
Campbell
K.
,
Joyner
A. L.
,
Rubenstein
J. L. R.
,
Martinez
S.
,
Martin
G. R.
(
1997
)
Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function.
Development
124
,
2923
2934
Williams
N. A.
,
Holland
P. W. H.
(
1996
)
Old head on young shoulders.
Nature
383
,
490
–.
Wray
G. A.
,
Levinton
J. S.
,
Shapiro
L. H.
(
1996
)
Molecular evidence for deep precambrian divergences among metazoan phyla.
Science
274
,
568
573
Xuan
S.
,
Baptista
C. A.
,
Balas
G.
,
Tao
W.
,
Soares
V. C.
,
Lai
E.
(
1995
)
Winged helix transcription factor BF-1 is essential for the development of the verebral hemispheres.
Neuron
14
,
1141
1152
Younossi-Hartenstein
A.
,
Green
P.
,
Liaw
G. J.
,
Rudolph
K.
,
Lengyel
J.
,
Hartenstein
V.
(
1997
)
Control of early neurogenesis of the Drosophila brain by the head gap genes tll, otd, ems and btd.
Dev. Biol
182
,
270
283
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