During mammalian development, the Cdx1 homeobox gene exhibits an early period of expression when the embryonic body axis is established, and a later period where expression is restricted to the embryonic intestinal endoderm. Cdx1 expression is maintained throughout adulthood in the proliferative cell compartment of the continuously renewed intestinal epithelium, the crypts. In this study, we provide evidence in vitro and in vivo that Cdx1 is a direct transcriptional target of the Wnt/(beta)-catenin signaling pathway. Upon Wnt stimulation, expression of Cdx1 can be induced in mouse embryonic stem (ES) cells as well as in undifferentiated rat embryonic endoderm. Tcf4-deficient mouse embryos show abrogation of Cdx1 protein in the small intestinal epithelium, making Tcf4 the likely candidate to transduce Wnt signal in this part of gut. The promoter region of the Cdx1 gene contains several Tcf-binding motifs, and these bind Tcf/Lef1/(beta)-catenin complexes and mediate (beta)-catenin-dependent transactivation. The transcriptional regulation of the homeobox gene Cdx1 in the intestinal epithelium by Wnt/(beta)-catenin signaling underlines the importance of this signaling pathway in mammalian endoderm development.
REFERENCES
Aberle
H.
, Schwartz
H.
, Kemler
R.
(1996
) Cadherin-catenin complex: Protein interactions and their implications for cadherin function.
J. Cell. Biochem
61
, 514
–523
Arnold
S.J.
, Stappert
J.
, Bauer
A.
, Kispert
A.
, Herrmann
B.G.
, Kemler
R.
(2000
) Brachyury is a target gene of the Wnt/-catenin signaling pathway.
Mech. Dev
91
, 249
–258
Behrens
J.
, von Kries
J.P.
, Kuhl
M.
, Bruhn
L.
, Wedlich
D.
, Grosschedl
R.
, Birchmeier
W.
(1996
) Functional interaction of beta-catenin with the transcription factor Lef1.
Nature
382
, 638
–642
Berx
G.
, Nollet
F.
, van Roy
F.
(1998
) Dysregulation of the E-cadherin/catenin complex by irreversible mutations in human carcinomas.
Cell Adhes. Commun
6
, 171
–184
Brabletz
T.
, Jung
A.
, Dag
S.
, Hlubek
F.
, Kirchner
T.
(1999
) beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer.
Am. J. Pathol
155
, 1033
–1038
Brannon
M.
, Gomperts
M.
, Sumoy
L.
, Moon
R.T.
, Kimelman
D.
(1997
) A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus.
Genes Dev
11
, 2359
–2370
Cadigan
K.M.
, Nusse
R.
(1997
) Wnt signaling: a common theme in animal development.
Genes Dev
11
, 3286
–3305
Calnek
D.
, Quaroni
A.
(1993
) Differential localization by in-situ hybridization of distinct keratin mRNA species during intestinal epithelial cell development and differentiation.
Differentiation
53
, 95
–104
Calvert
R.
, Pothier
P.
(1990
) Migration of fetal intestinal intervillous cells in neonatal mice.
Anat. Record
227
, 199
–206
Cavallo
R.A.
, Cox
R.T.
, Moline
M.M.
, Roose
J.
, Polevoy
G.A.
, Clevers
H.
, Peifer
M.
, Bejsovec
A.
(1998
) Drosophila Tcf and Groucho interact to repress Wingless signalling activity.
Nature
395
, 604
–608
Chawengsaksophak
K.
, James
R.
, Hammond
V.E.
, Köntgen
F.
, Beck
F.
(1997
) Homeosis and intestinal tumours in Cdx2 mutant mice.
Nature
386
, 84
–87
da Costa
L.T.
, He
T.C.
, Yu
J.
, Sparks
A.B.
, Morin
P.J.
, Polyak
K.
, Laken
S.
, Vogelstein
B.
, Kinzler
K.W.
(1999
) CDX2 is mutated in a colorectal cancer with normal APC/beta-catenin signaling.
Oncogene
18
, 5010
–5014
Duluc
I.
, Lorentz
O.
, Fritsch
C.
, Leberquier
C.
, Kedinger
M.
, Freund
J.N.
(1997
) Changing intestinal connective tissue interactions alters homeobox gene expression in epithelial cells.
J. Cell Sci
110
, 1317
–1324
Duprey
P.
, Chowdhury
K.
, Dressler
G.R.
, Balling
R.
, Simon
D.
, Guenet
J.L.
, Gruss
P.
(1988
) A mouse gene homologous to the Drosophila gene caudal is expressed in epithelial cells from the embryonic intestine.
Genes Dev
2
, 1647
–1654
Freund
J.N.
, Domon-Dell
C.
, Kedinger
M.
, Duluc
I.
(1998
) The Cdx1 and Cdx2 homeobox genes in the intestine.
Biochem. Cell Biol
76
, 957
–969
Grapin-Botton
I.
, Melton
D.A.
(2000
) Endoderm development: from patterning to organogenesis.
Trends Genet
16
, 124
–130
Gumbiner
B.M.
(1998
) Propagation and localization of Wnt signaling.
Curr. Opin. Genet. Dev
8
, 430
–435
He
T.C.
, Sparks
A.B.
, Rago
C.
, Hermeking
H.
, Zawel
L.
, da Costa
L.T.
, Morin
P.J.
, Vogelstein
B.
, Kinzler
K.W.
(1998
) Identification of c-MYC as a target of the APC pathway.
Science
281
, 1509
–1512
Hecht
A.
, Litterst
C.M.
, Huber
O.
, Kemler
R.
(1999
) Functional characterization of multiple transactivating elements in beta-catenin, some of which interact with the TATA-binding protein in vitro.
J. Biol. Chem
274
, 18017
–18025
Hecht
A.
, Vleminckx
K.
, Stemmler
M.P.
, van Roy
F.
, Kemler
R.
(2000
) The p300/CBP acetyltransferase function as transcriptional coactivators of-catenin in vertebrates.
EMBO J
19
, 1
–13
Huber
O.
, Bierkamp
C.
, Kemler
R.
(1996
) Cadherins and Catenins In Development.
Curr. Opin. Cell Biol
8
, 685
–691
Huber
O.
, Korn
R.
, McLaughlin
J.
, Ohsugi
M.
, Herrmann
B.G.
, Kemler
R.
(1996
) Nuclear localization of beta-catenin by interaction with transcription factor Lef1.
Mech. Dev
59
, 3
–10
James
R.
, Kazenwadel
J.
(1991
) Homeobox gene expression in the intestinal epithelium of adult mice.
J. Biol. Chem
266
, 3246
–3251
Kinzler
K.W.
, Vogelstein
B.
(1996
) Lessons from hereditary colorectal cancer.
Cell
87
, 159
–170
Kispert
A.
, Vainio
S.
, McMahon
A.P.
(1998
) Wnt4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney.
Development
125
, 4225
–4234
Korinek
V.
, Barker
N.
, Willert
K.
, Molenaar
M.
, Roose
J.
, Wagenaar
G.
, Markman
M.
, Lamers
W.
, Destree
O.
, Clevers
H.
(1998
) Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse.
Mol. Cell Biol
18
, 1248
–1256
Krumlauf
R.
(1994
) Hox genes in vertebrate development.
Cell
78
, 191
–201
Lorentz
O.
, Cadoret
A.
, Duluc
I.
, Capeau
J.
, Gespach
C.
, Freund
J.N.
(1999
) Downregulation of the colon tumor-suppressor homeobox gene Cdx2 by oncogenic ras.
Oncogene
18
, 87
–92
Lorentz
O.
, Duluc
I.
, Arcangelis
A.D.
, Simon-Assmann
P.
, Kedinger
M.
, Freund
J.N.
(1997
) Key role of the Cdx2 homeobox gene in extracellular matrix-mediated intestinal cell differentiation.
J. Cell Biol
139
, 1553
–1565
Macdonald
P.M.
, Struhl
G.
(1986
) A molecular gradient in early Drosophila embryos and its role in specifying the body pattern.
Nature
324
, 537
–545
Mann
B.
, Gelos
M.
, Siedow
A.
, Hanski
M.L.
, Gratchev
A.
, Ilyas
M.
, Bodmer
W.F.
, Moyer
M.P.
, Riecken
E.O.
, Buhr
H.J.
, Hanski
C.
(1999
) Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas.
Proc. Natl. Acad. Sci. USA
96
, 1603
–1608
Mathan
M.
, Moxey
P.C.
, Trier
J.S.
(1976
) Morphogenesis of fetal rat duodenal villi.
Am. J. Anat
146
, 73
–92
McGinnis
W.
, Krumlauf
R.
(1992
) Homeobox genes and axial patterning.
Cell
68
, 283
–302
Meyer
B.I.
, Gruss
P.
(1993
) Mouse Cdx1 expression during gastrulation.
Development
117
, 191
–203
Molenaar
M.
, Vandewetering
M.
, Oosterwegel
M.
, Peterson-Maduro
J.
, Godsave
S.
, Korinek
V.
, Roose
J.
, Destree
O.
, Clevers
H.
(1996
) Xtcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos.
Cell
86
, 391
–399
Moon
R.T.
, Brown
J.D.
, Torres
M.
(1997
) WNTs modulate cell fate and behavior during vertebrate development.
Trends Genet
13
, 157
–162
Moon
R.T.
, Kimelman
D.
(1998
) From cortical rotation to organizer gene expression, toward a molecular explanation of axis specification in Xenopus.
BioEssays
20
, 536
–545
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 host genome.
Cell
31
, 99
–109
Peifer
M.
, Polakis
P.
(2000
) Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus.
Science
287
, 1606
–1609
Polakis
P.
(1999
) The oncogenic activation of beta-catenin.
Curr. Opin. Genet. Dev
9
, 15
–21
Ren
P.
, Silberg
D.G.
, Sirica
A.E.
(2000
) Expression of an intestine-specific transcription factor (CDX1) in intestinal metaplasia and in subsequently developed intestinal type of cholangiocarcinoma in rat liver.
Am. J. Pathol
156
, 621
–627
Riese
J.
, Yu
X.
, Munnerlyn
A.
, Eresh
S.
, Hsu
S.C.
, Grosschedl
R.
, Bienz
M.
(1997
) Lef1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic.
Cell
88
, 777
–787
Roose
J.
, Molenaar
M.
, Peterson
J.
, Hurenkamp
J.
, Brantjes
H.
, Moerer
P.
, van de Wetering
M.
, Destree
O.
, Clevers
H.
(1998
) The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors.
Nature
395
, 608
–612
Roose
J.
, Huls
G.
, van Beest
M.
, Moerer
P.
, van der Horn
K.
, Goldschmeding
R.
, Logtenberg
T.
, Clevers
H.
(1999
) Synergy between tumor suppressor APC and the beta-catenin-Tcf target Tcf1.
Science
285
, 1923
–1926
Shtutman
M.
, Zhurinsky
J.
, Simcha
I.
, Albanese
C.
, D'Amico
M.
, Pestell
R.
, Ben-Ze'ev
A.
(1999
) The cyclinD1 gene is a target of the beta-catenin/Lef1 pathway.
Proc. Natl. Acad. Sci. USA
96
, 5522
–5527
Silberg
D.G.
, Furth
E.E.
, Taylor
J.K.
, Schuck
T.
, Chiou
T.
, Traber
P.G.
(1997
) CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium.
Gastroenterol
113
, 478
–486
Soubeyran
P.
, Andre
F.
, Lissitzki
J.C.
, Mallo
G.V.
, Moucadel
V.
, Roccabianca
M.
, Rechreche
H.
, Marvaldi
J.
, Dikic
I.
, Dagorn
J.C.
, Iovanna
J.L.
(1999
) Cdx1 promotes differentiation in a rat intestinal epithelial cell line.
Gastroenterol
117
, 1326
–1338
Subramanian
V.
, Meyer
B.
, Evans
G.S.
(1998
) The murine Cdx1 gene product localises to the proliferative compartment in the developing and regenerating intestinal epithelium.
Differentiation
64
, 11
–18
Subramanian
V.
, Meyer
B.I.
, Gruss
P.
(1995
) Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes.
Cell
83
, 641
–653
Tetsu
O.
, McCormick
F.
(1999
) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
Nature
398
, 422
–426
Waltzer
L.
, Bienz
M.
(1998
) Drosophila CBP represses the transcription factor Tcf to antagonize Wingless signalling.
Nature
395
, 521
–525
Willert
K.
, Nusse
R.
(1998
) Beta-catenin: a key mediator of Wnt signaling.
Curr. Opin. Genet. Dev
8
, 95
–102
Wodarz
A.
, Nusse
R.
(1998
) Mechanisms of Wnt signaling in development.
Annu. Rev. Cell Dev. Biol
14
, 59
–88
Yamaguchi
T.P.
, Takada
S.
, Yoshikawa
Y.
, Wu
N.
, McMahon
A.P.
(1999
) T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification.
Genes Dev
13
, 3185
–3190
Yost
C.
, Torres
M.
, Miller
R.R.
, Huang
E.
, Kimelman
D.
, Moon
R.T.
(1996
) The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3.
Genes Dev
10
, 1443
–1454
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