Clim-2 (NLI, Lbd1) is one of two related mouse proteins that interact with Lim-domain homeoproteins. In the mouse, embryonic expression of Clim-2 is particularly pronounced in facial ectomesenchyme and limb bud mesenchyme in association with Lim genes, Lhx-6 and Lmx-1 respectively. We show that in common with both these Lim genes, Clim-2 expression is regulated by signals from overlying epithelium. In both the developing face and the limb buds we identify Fgf-8 as the likely candidate signalling molecule that regulates Clim-2 expression. We show that in the mandibular arch, as in the limb, Fgf-8 functions in combination with CD44, a cell surface binding protein, and that blocking CD44 binding results in inhibition of Fgf8-induced expression of Clim-2 and Lhx-6. Regulation of gene expression by Fgf8 in association with CD44 is thus conserved between limb and mandibular arch development.

Reference

Åberg
T.
,
Wozney
J.
,
Thesleff
I.
(
1997
)
Expression patterns of bone morphogenetic proteins (Bmps) in the developing mouse tooth suggest roles in morphogenesis and cell differentiation.
Dev. Dyn
210
,
383
396
Agulnick
A. D.
,
Taira
M.
,
Breen
J. J.
,
Tanaka
T.
,
Dawid
I. B.
,
Westphal
H.
(
1996
)
Interactions of the Lim-domain-binding factor Ldb1 with Lim homeodomain proteins.
Nature
384
,
270
272
Bach
I.
,
Carriere
C.
,
Ostendorff
H. P.
,
Andersen
B.
,
Rosenfeld
M.G.
(
1997
)
A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins.
Genes Dev
11
,
1370
1380
Breen
J. J.
,
Agulnick
A. D.
,
Westphal
S.
,
Dawid
I. B.
(
1998
)
Interactions between LIM domains and the LIM domain-binding protein Ldb1.
J. Biol. Chem
273
,
4712
4717
Brown
J. M.
,
Wedden
S. E.
,
Millburn
G. H.
,
Robson
L. G.
,
Hill
R. E.
,
Davidson
D. R.
,
Tickle
C.
(
1993
)
Experimental-analysis of the control of expression of the homeobox-gene Msx-1 in the developing limb and face.
Development
119
,
41
48
Buckland
R. A.
,
Collinson
J. M.
,
Graham
E.
,
Davidson
D. R.
,
Hill
R. E.
(
1998
)
Antagonistic effects of FGF4 on BMP induction of apoptosis and chondrogenesis in the chick limb bud.
Mech. Dev
71
,
143
150
Bulfone
A.
,
Kim
H. J.
,
Puelles
L.
,
Porteus
M. H.
,
Grippo
J. F.
,
Rubenstein
J. L. R.
(
1993
)
The mouse Dlx-2 (Tes-1) gene is expressed in spatially restricted domains of the forebrain, face and limbs in midgestation mouse embryos.
Mech. Dev
40
,
129
140
Celli
G.
,
LaRochelle
W. J.
,
Mackem
S.
,
Sharp
R.
,
Merlino
G.
(
1998
)
Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning.
EMBO J
17
,
1642
1655
Chen
Y. P.
,
Bei
M.
,
Woo
I.
,
Satokata
I.
,
Maas
R.
(
1996
)
Msx1 controls inductive signaling in mammalian tooth morphogenesis.
Development
122
,
3035
3044
Chen
Y. P.
,
Satokata
I.
,
Heaney
S.
,
Woo
I.
,
Maas
R.
(
1997
)
Control of limb bud pattern formation and apoptosis by mouse Msx genes.
Dev. Biol
186
,
228
–.
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 embryo.
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
Cygan
J. A.
,
Johnson
R. L.
,
McMahon
A. P.
(
1997
)
Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En-1 mutants.
Development
124
,
5021
5032
Dawid
I. B.
,
Breen
J. J.
,
Toyama
R.
(
1998
)
LIM domains: multiple roles as adapters and functional modifiers in protein interactions.
Trends Genet
14
,
156
162
Ferrari
D.
,
Sumoy
L.
,
Gannon
J.
,
Sun
H. L.
,
Brown
A. M. C.
,
Upholt
W. B.
,
Kosher
R. A.
(
1995
)
The expression pattern of the distal-less homeobox-containing gene Dlx-5 in the developing chick limb bud suggests its involvement in apical ectodermal ridge activity, pattern-formation, and cartilage differentiation.
Mech. Dev
52
,
257
264
Francis
P. H.
,
Richardson
M. K.
,
Brickell
P. M.
,
Tickle
C.
(
1994
)
Bone morphogenetic proteins and a signaling pathway that controls patterning in the developing chick limb.
Development
120
,
209
218
Grigoriou
M.
,
Tucker
A. S.
,
Sharpe
P. T.
,
Pachnis
V.
(
1998
)
Expression of Lhx-6 and Lhx-7, a novel subfamily of Lim homeodomain genes, suggests a role in mammalian head development.
Development
125
,
2063
2074
Hardcastle
Z.
,
Rong
M.
,
Chi-chung
H.
,
Sharpe
P. T.
(
1998
)
The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants.
Development
125
,
2803
2811
Heikinheimo
M.
,
Lawshe
A.
,
Shackleton
G. M.
,
Wilson
D. B.
,
MacArthur
C. A.
(
1994
)
Fgf-8 expression in the post-gastrulation mouse suggests roles in the developing face, limbs and central nervous system.
Mech. Dev
48
,
129
138
Jernvall
J.
,
Kettunen
P.
,
Karavanova
I.
,
Martin
L. B.
,
Thesleff
I.
(
1994
)
Evidence for the role of the Enamel Knot as a control center in mammalian tooth cusp formation—Nondividing cells express growth-stimulating Fgf-4 gene.
Int. J. Dev. Biol
38
,
463
469
Jones
C. M.
,
Lyons
K. M.
,
Hogan
B. L. M.
(
1991
)
Involvement of Bone-Morphogenetic Protein-4 (Bmp-4) and Vgr-1 in morphogenesis and neurogenesis in the mouse.
Development
111
,
531
–.
Jurata
L. W.
,
Kenny
D. A.
,
Gill
G. N.
(
1996
)
Nuclear Lim Interactor, a rhombotin and Lim homeodomain interacting protein, is expressed early in neuronal development.
Proc. Nat. Acad. Sci. USA
93
,
11693
11698
Kettunen
P.
,
Thesleff
I.
(
1998
)
Expression and function of FGFs-4,-8, and-9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis.
Dev. Dyn
211
,
256
268
Kitanaka
J. I.
,
Takemura
M.
,
Matsumoto
K.
,
Mori
T.
,
Wanaka
A.
(
1998
)
Structure and chromosomal localization of a murine Lim/homeobox gene, Lhx-8.
Genomics
49
,
307
309
Koyama
E.
,
Yamaai
T.
,
Iseki
S.
,
Ohuchi
H.
,
Nohno
T.
,
Yoshioka
H.
,
Hayashi
Y.
,
Leatherman
J. L.
,
Golden
E. B.
,
Noji
S.
, et al. 
(
1996
)
Polarizing activity, sonic hedgehog, and tooth development in embryonic and postnatal mouse.
Dev. Dyn
206
,
59
72
Lyons
K. M.
,
Pelton
R. W.
,
Hogan
B. L. M.
(
1990
)
Organogenesis and pattern-formation in the mouse—RNA distribution patterns suggest a role for Bone Morphogenetic Protein-2a (Bmp-2a).
Development
109
,
833
–.
Martin
G. R.
(
1998
)
The roles of FGFs in the early development of vertebrate limbs.
Genes Dev
12
,
1571
1586
Meyers
E. N.
,
Lewandoski
M.
,
Martin
G. R.
(
1998
)
Generation of an Fgf-8 mutant allelic series using a single targeted mouse line carrying Cre and Flp recombinase recognition sites.
Nature Genet
18
,
136
141
Morcillo
P.
,
Rosen
C.
,
Baylies
M. K.
,
Dorsett
D.
(
1997
)
Chip, a widely expressed chromosomal protein required for segmentation and activity of a remote wing margin enhancer in Drosophila.
Genes Dev
11
,
2729
2740
Neubuser
A.
,
Peters
H.
,
Balling
R.
,
Martin
G. R.
(
1997
)
Antagonistic interactions between FGF and BMP signaling pathways: A mechanism for positioning the sites of tooth formation.
Cell
90
,
247
255
Ponta
H.
,
Wainwright
D.
,
Herrlich
P.
(
1998
)
The CD44 protein family.
Int. J. Biochem. Cell Biol
30
,
299
305
Pownall
M. E.
,
Tucker
A. S.
,
Slack
J. M. W.
,
Isaacs
H. V.
(
1996
)
eFGF, Xcad3 and Hox genes form a molecular pathway that establishes the anteroposterior axis in Xenopus.
Development
122
,
3881
3892
Qiu
M. S.
,
Bulfone
A.
,
Martinez
S.
,
Meneses
J. J.
,
Shimamura
K.
,
Pedersen
R. A.
,
Rubenstein
J. L. R.
(
1995
)
Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and 2nd branchial arch derivatives and abnormal differentiation in the forebrain.
Genes Dev
9
,
2523
2538
Rahmanian
M.
,
Pertoft
H.
,
Kanda
S.
,
Christofferson
R.
,
Claesson Welsh
L.
,
Heldin
P.
(
1997
)
Hyaluronan oligosaccharides induce tube formation of a brain endothelial cell line in vitro.
Exp. Cell Res
237
,
223
230
Riddle
R. D.
,
Ensini
M.
,
Nelson
C.
,
Tsuchida
T.
,
Jessell
T. M.
,
Tabin
C.
(
1995
)
Induction of the Lim homeobox gene Lmx1 by Wnt7a establishes dorsoventral pattern in the vertebrate limb.
Cell
83
,
631
640
Saxen
L.
(
1966
)
The effect of Tetracyclin on osteogenesis in vitro.
J. exp. Zool
162
,
269
294
Sheng
H. Z.
,
Zhadanov
A. B.
,
Mosinger
B.
Jr
,
Fujii
T.
,
Bertuzzi
S.
,
Grinberg
A.
,
Lee
E. J.
,
Huang
S.-P.
,
Mahon
K. A.
,
Westphal
H.
(
1996
)
Specification of pituitary cell lineages by the Lim homeobox gene Lhx-3.
Science
272
,
1004
1007
Sherman
L.
,
Wainwright
D.
,
Ponta
H.
,
Herrlich
P.
(
1998
)
A splicevariant of CD44 expressed in the apical ectodermal ridge presents to limb mesenchyme and is required for limb outgrowth.
Genes Dev
12
,
1058
1071
Skelton
T. P.
,
Zeng
C. X.
,
Nocks
A.
,
Stamenkovic
I.
(
1998
)
Glycosylation provides both stimulatory and inhibitory effects on cell surface and soluble CD44 binding to hyaluronan.
J. Cell Biol
140
,
431
446
Toyama
R.
,
Kobayashi
M.
,
Tomita
T.
,
Dawid
I. B.
(
1998
)
Expression of LIM-domain binding protein (ldb) genes during zebrafish embryogenesis.
Mech. Dev
71
,
197
200
Treier
M.
,
Gleiberman
A. S.
,
O'Connell
S. M.
,
Szeto
D. P.
,
McMahon
J. A.
,
McMahon
A. P.
,
Rosenfeld
M. G.
(
1998
)
Multistep signaling requirements for pituitary organogenesis in vivo.
Genes Dev
12
,
1691
1704
Trowel
O. A.
(
1959
)
The culture of mature organs in a synthetic medium.
Exp. Cell Res
16
,
118
147
Tucker
A. S.
,
Al Khamis
A.
,
Sharpe
P. T.
(
1998
)
Interactions between Bmp-4 and Msx-1 act to restrict gene expression to odontogenic mesenchyme.
Dev. Dyn
212
,
533
539
Tucker
A. S.
,
Yamada
G.
,
Grigoriou
M.
,
Pachnis
V.
,
Sharpe
P. T.
(
1999
)
Fgf-8 determines rostral-caudal polarity in the first branchial arch.
Development
126
,
11
51
Vaahtokari
A.
,
Åberg
T.
,
Jernvall
J.
,
Keranen
S.
,
Thesleff
I.
(
1996
)
The enamel knot as a signaling center in the developing mouse tooth.
Mech. Dev
54
,
39
43
Vogel
A.
,
Rodriguez
C.
,
Warnken
W.
,
Izpisua Belmonte
J. C.
(
1995
)
Dorsal cell fate specified by chick Lmx-1 during vertebrate limb development.
Nature
378
,
716
720
Wanaka
A.
,
Matsumoto
K.
,
Kashihara
Y.
,
Furuyama
T.
,
Tanaka
T.
,
Mori
T.
,
Tanno
Y.
,
Yokoya
S.
,
Kitanaka
J.
,
Takemura
M.
, et al. 
(
1997
)
LIM-homeodomain gene family in neural development.
Dev. Neurosci
19
,
97
100
Wheatley
S. C.
,
Isacke
C. M.
,
Crossley
P. H.
(
1993
)
Restricted expression of the hyaluronan receptor, CD44, during postimplantation mouse embryogenesis suggests key roles in tissue formation and patterning.
Development
119
,
295
306
Yu
Q.
,
Grammatikakis
N.
,
Toole
B. P.
(
1996
)
Expression of multiple CD44 isoforms in the apical ectodermal ridge of the embryonic mouse limb.
Dev. Dyn
207
,
204
214
Yu
Q.
,
Toole
B. P.
(
1997
)
Common pattern of CD44 isoforms expressed in morphogenetically active epithelia.
Dev. Dyn
208
,
1
10
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