The analysis of mutant alleles at the Wnt-1 locus has demonstrated that Wnt-1-mediated cell signalling plays a critical role in development of distinct regions of the embryonic central nervous system (CNS). To determine how these signals participate in the formation of the CNS, we have ectopically expressed this factor in the spinal cord under the control of the Hoxb-4 Region A enhancer. Ectopic Wnt-1 expression causes a dramatic increase in the number of cells undergoing mitosis in the ventricular region and a concomitant ventricular expansion. Although this leads to consistent changes in the relative proportions of dorsal and ventral regions, Wnt-1 does not appear to act as a primary patterning signal. Rather, our experiments indicate that Wnt-1 can act as a mitogen in the developing CNS.

REFERENCES

Altshuler
D.
,
Cepko
C.
(
1992
)
A temporally regulated, diffusible activity is required for rod photoreceptor development in vitro.
Development
114
,
947
957
Alvarado-Mallart
R.-M.
,
Martinez
S.
,
Lance-Jones
C. C.
(
1990
)
Pluripotentiality of the 2-day-old germinative neuroepithelium.
Dev. Biol
139
,
75
88
Boulder Committee
(
1970
)
Embryonic vertebrate central nervous system: revised terminology.
Anat. Rec
166
,
257
261
Bradley
R. S.
,
Brown
A. M. C.
(
1990
)
The proto-oncogene int −1 encodes a secreted protein associated with the extracellular matrix.
EMBO J
9
,
1569
1575
Brown
A. M. C.
,
Wildin
R. S.
,
Prendergast
T. J.
,
Varmus
H. E.
(
1986
)
A retrovirus vector expressing the putative mammary oncogene int- 1 causes partial transformation of a mammary epithelial cell line.
Cell
46
,
1001
1009
Ericson
J.
,
Thor
S.
,
Edlund
T.
,
Jessell
T. M.
,
Yamada
T.
(
1992
)
Early stages of motor neuron differentiation revealed by expression of homeobox gene Islet-1.
Science
256
,
1555
1560
Gavin
B.
,
McMahon
J. A.
,
McMahon
A. P.
(
1990
)
Expression of multiple novel Wnt-1 / int −1 related genes during fetal and adult mouse development.
Genes Dev
4
,
2319
2332
Gonzalez
F.
,
Swales
I.
,
Bejsovec
A.
,
Skaer
H.
,
Martinez-Arias
A.
(
1991
)
Secretion and movement of the wingless protein in the epidermis of the Drosophila embryo.
Mech. Dev
35
,
43
54
Goulding
M. D.
,
Chalepakis
G.
,
Deutsch
U.
,
Erselius
J. R.
,
Gruss
P.
(
1991
)
Pax −3, a novel murine DNA binding protein is expressed during early neurogenesis.
EMBO J
10
,
1135
1147
Goulding
M. D.
,
Lumsden
A.
,
Gruss
P.
(
1993
)
Signals from the notochord and floor plate regulate the region-specific expression of two Pax genes in the developing spinal cord.
Development
117
,
1001
1016
Graham
A.
,
Papalopulu
N.
,
Lorimer
J.
,
McVey
J. H.
,
Tuddenham
E. G.
,
Krumlauf
R.
(
1988
)
Characterization of a murine homeo box gene, Hox −2. 6 related to the Drosophila Deformed gene.
Genes Dev
2
,
1424
1438
Graham
A.
,
Maden
M.
,
Krumlauf
R.
(
1991
)
The murine Hox −2 genes display dynamic dorsoventral patterns of expression during central nervous system development.
Development
112
,
255
264
Gruss
P.
,
Walther
C.
(
1992
)
Pax genes in development.
Cell
69
,
719
722
Hanley
T.
,
Merlie
J. P.
(
1991
)
Transgene detection in unpurified mouse tail DNA by polymerase chain reaction.
Biotechniques
10
,
56
–.
Huang
E. J.
,
Nocka
K. H.
,
Buck
J.
,
Besmer
P.
(
1992
)
Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2.
Mol. Biol. Cell
3
,
349
362
Itasaki
N.
,
Ichijo
H.
,
Hama
C.
,
Matsuno
T.
,
Nakamura
H.
(
1991
)
Establishment of rostrocaudal polarity in tectal primordia: engrailed expression and subsequent tectal polarity.
Development
113
,
1133
1144
Jones
C. M.
,
Lyons
K. M.
,
Hogan
B. L. M.
(
1991
)
Involvement of bone morphogenetic protein-4 and Vgr-1 in morphogenesis and neurogenesis in the mouse.
Development
111
,
531
542
Jue
S. F.
,
Bradley
R. S.
,
Rudnicki
J. A.
,
Varmus
H. E.
,
Brown
A. M. C.
(
1992
)
The mouse Wnt-1 gene can act via a paracrine mechanism in transformation of mammary epithelial cells.
Mol. Cell Biol
12
,
321
328
Karlsson
O.
,
Thor
S.
,
Norberg
T.
,
Ohlsson
H.
,
Edlund
T.
(
1990
)
Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo and a Cys-His domain.
Nature
344
,
879
882
Keshet
E.
,
Lyman
S. D.
,
Williams
D. E.
,
Anderson
D. M.
,
Jenkins
N. A.
,
Copeland
N. G.
,
Parada
L. F.
(
1991
)
Embryonic RNA expression patterns of the c-kit receptor and its cognate ligand suggest multiple functional roles in mouse development.
EMBO J
10
,
2425
2435
Lyons
K.
,
Graycar
J. L.
,
Lee
A.
,
Hashmi
S.
,
Lindquist
P. B.
,
Chen
E. Y.
,
Hogan
B. L. M.
,
Derynck
R.
(
1989
)
Vgr −1, a mammalian gene related to Xenopus Vg −1, is a member of the transforming growth factorgene superfamily.
Proc. Natl. Acad. Sci. USA
86
,
4554
4558
Martinez
S.
,
Wassef
M.
,
Alvarado-Mallart
R.-M.
(
1991
)
Induction of mesencephalic phenotype in 2-day-old chick prosncephalon is preceded by the early expression of the homeobox gene en.
Neuron
6
,
971
981
Matsui
Y.
,
Zsebo
K. M.
,
Hogan
B. L. M.
(
1990
)
Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c -kit.
Nature
347
,
677
9
McConnell
S. K.
,
Kaznowski
C. E.
(
1991
)
Cell cycle dependence of laminar determination in developing neocortex.
Science
254
,
282
285
McGrew
L. L.
,
Otte
A. P.
,
Moon
R. T.
(
1992
)
Analysis of Xwnt −4 in embryos of Xenopus laevis: A Wnt family member expressed in the brain and floor plate.
Development
115
,
463
473
McMahon
A. P.
,
Bradley
A.
(
1990
)
The Wnt-1 (int −1) protooncogene is required for the development of a large region of the mouse brain.
Cell
62
,
1073
1085
McMahon
A. P.
(
1992
)
The Wnt family of developmental regulators.
Trends Genet
8
,
1
4
McMahon
A. P.
,
Joyner
A. L.
,
Bradley
A.
,
McMahon
J. A.
(
1992
)
The midbrain-hindbrain phenotype of Wnt-1 / Wnt-1 mice results from the stepwise deletion of engrailed -expressing cells by 9. 5 days postcoitum.
Cell
69
,
581
595
Miller
M. W.
,
Nowakowski
R. S.
(
1988
)
Use of bromodeoxyuridine immunohistochemistry to examine the proliferation, migration and time of origin of cells in the central nervous system.
Brain Res
457
,
44
52
Moon
R. T.
(
1993
)
In pursuit of the functions of the Wnt family of developmental regulators: Insights from Xenopus laevis.
BioEssays
15
,
91
97
Nakamura
H.
(
1990
)
Do CNS anlagen have plasticity in differentiation? Anlaysis in quail-chick chimera.
Brain Res
511
,
122
128
Nornes
H. O.
,
Carry
M.
(
1978
)
Neurogenesis in spinal cord of mouse: an autoradiographic analysis.
Brain Res
159
,
1
6
Nusse
R.
,
Varmus
H. E.
(
1982
)
Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the mouse genome.
Cell
31
,
99
109
Nusse
R.
,
Theunissen
H.
,
Wagenaar
E.
,
Rijsewijk
F.
,
Gennissen
A.
,
Otte
A.
,
Schuuring
E.
,
Van Ooyen
A.
(
1990
)
The wnt −1 (int −1) oncogene promoter and its mechanism of activation by insertion of proviral DNA of the mouse mammary tumor virus.
Mol. Cell. Biol
10
,
4170
4179
Nusse
R.
,
Varmus
H. E.
(
1992
)
Wnt genes.
Cell
69
,
1073
1087
Papkoff
J.
,
Schryver
B.
(
1990
)
Secreted int-1 protein is associated with the cell surface.
Molec. Cell Biol
10
,
2723
2730
Parr
B.
,
Shea
M.
,
Vassileva
G.
,
McMahon
A. P.
(
1993
)
Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds.
Development
119
,
247
261
Roelink
H.
,
Nusse
R.
(
1991
)
Expression of two members of the Wnt family during mouse development--restricted temporal and spatial patterns in the developing neural tube.
Genes Dev
5
,
381
388
Salinas
P. C.
,
Nusse
R.
(
1992
)
Regional expression of the Wnt −3 gene in the developing mouse forebrain in relation to diencephalic neuromeres.
Mech. Dev
39
,
151
160
Sanes
J. R.
(
1993
)
Topographic maps and molecular gradients.
Curr. Opin. Neur
3
,
67
74
Schoenwolf
G. C.
,
Smith
J. L.
(
1990
)
Mechanisms of neuralation: Traditional viewpoint and recent advances.
Development
109
,
243
270
Skaer
H.
,
Martinas Arias
A.
(
1992
)
The wingless product is required for cell proliferation in the Malphigian tubule anlage of Drosophila melanogaster.
Development
116
,
745
754
Storey
K. G.
,
Crossley
J. M.
,
DeRobertis
E. M.
,
Norris
W. E.
,
Stern
C. D.
(
1992
)
Neural induction and regionalisation of the chick embryo.
Development
114
,
729
741
Thomas
K. R.
,
Capecchi
M. R.
(
1990
)
Targeted disruption of the murine int −1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development.
Nature
346
,
847
850
Tsukamoto
A. S.
,
Grosschedl
R.
,
Guzman
R. C.
,
Parslow
T.
,
Varmus
H. E.
(
1988
)
Expression of the int −1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice.
Cell
55
,
619
625
Turner
D. L.
,
Snyder
E. Y.
,
Cepko
C. L.
(
1990
)
Lineage-independent determination of cell type in the embryonic mouse retina.
Neuron
4
,
833
845
Van den Heuvel
M.
,
Nusse
R.
,
Johnston
P.
,
Lawrence
P. A.
(
1989
)
Distribution of the wingless gene product in Drosophila embryos: a protein in involved in cell-cell communication.
Cell
59
,
739
749
van Ooyen
A.
,
Nusse
R.
(
1984
)
Structure and nucleotide sequence of the putative mammary oncogene int −1; proviral insertions leave the protein-encoding domain in tact.
Cell
39
,
233
240
van Straaten
H. W. M.
,
Hekking
J. W. M.
,
Wiertz-Hoessels
E. L.
,
Thors
F.
,
Drukker
J.
(
1988
)
Effect of notochord on the differentiation of a floor plate area in the neural tube of the chick embryo.
Anat. Embryol
177
,
317
324
Walther
C.
,
Gruss
P.
(
1991
)
Pax- 6, a murine paired box gene, is expressed in the developing CNS.
Development
113
,
1435
1449
Whiting
J.
,
Marshall
H.
,
Cook
M.
,
Krumlauf
R.
,
Rigby
P. W.
,
Stott
D.
,
Allemann
R. K.
(
1991
).
Multiple spatially specific enhancers are required to reconstruct the pattern of Hox-2.6 gene expression.
Genes. Dev
5
,
2048
2059
Wilkinson
D. G.
,
Bailes
J. A.
,
McMahon
A. P.
(
1987
)
Expression of the proto-oncogene int −1 is restricted to specific neural cells in the developing mouse embryo.
Cell
50
,
79
88
Yamada
T.
,
Placzek
M.
,
Tanaka
H.
,
Dodd
J.
,
Jessell
T. M.
(
1991
)
Control of cell pattern in the developing nervous system: Polarizing activity of the floor plate and notochord.
Cell
64
,
635
647
Zákány
J.
,
Duboule
D.
(
1993
)
Correlation of expression of Wnt-1 in developing limbs with abnormalities in growth and skeletal patterning.
Nature
362
,
546
549
This content is only available via PDF.