The molecular events of odontogenic induction are beginning to be elucidated, but until now nothing was known about the molecular basis of the patterning of the dentition. A role for Dlx-1 and Dlx-2 genes in patterning of the dentition has been proposed with the genes envisaged as participating in an ‘odontogenic homeobox gene code’ by specifying molar development. This proposal was based on the restricted expression of the genes in molar ectomesenchyme derived from cranial neural crest cells prior to tooth initiation. Mice with targeted null mutations of both Dlx-1 and Dlx-2 homeobox genes do not develop maxillary molar teeth but incisors and mandibular molars are normal. We have carried out heterologous recombinations between mutant and wild-type maxillary epithelium and mesenchyme and show that the ectomesenchyme underlying the maxillary molar epithelium has lost its odontogenic potential. Using molecular markers of branchial arch neural crest (Barx1) and commitment to chondrogenic differentiation (Sox9), we show that this population alters its fate from odontogenic to become chondrogenic. These results provide evidence that a subpopulation of cranial neural crest is specified as odontogenic by Dlx-1 and Dlx-2 genes. Loss of function of these genes results in reprogramming of this population of ectomesenchyme cells into chondrocytes. This is the first indication that the development of different shaped teeth at different positions in the jaws is determined by independent genetic pathways.

REFERENCES

REFERENCES
Bitgood
M. J.
,
McMahon
A. P.
(
1995
)
Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo.
Dev. Biol
172
,
126
138
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
Butler
P. M.
(
1956
)
The ontogeny of molar pattern.
Biol. Rev
31
,
30
70
Chen
Y. P.
,
Bei
M.
,
Woo
I.
,
Satokata
I.
,
Maas
R.
(
1996
)
Msx-1 controls inductive signalling in mammalian tooth morphogenesis.
Development
122
,
3035
3044
Ferrari
D.
,
Sumay
I.
,
Gannon
J.
,
Sun
H.L.
,
Brown
A.M.C.
,
Upholt
W.B.
,
Kosher
A.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
Goodrich
L. V.
,
Johnson
R. L.
,
Milenkovic
L.
,
McMahon
J. A.
,
Scott
M. P.
(
1996
)
Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog.
Genes Dev
10
,
301
312
Imai
H.
,
Osumi-Yamashita
N.
,
Ninomiya
Y.
,
Eto
K.
(
1996
)
Contribution of early-emigrating midbrain crest cells to the dental mesenchyme of mandibular molar teeth in rat embryos.
Dev. Biol
176
,
151
165
Kollar
E. J.
,
Baird
G. R.
(
1969
)
The influence of the dental papilla on the development of tooth shape in embryonic mouse tooth germs.
J. Embryol. Exp. Morphol
21
,
131
–.
Lumsden
A. G. S.
(
1988
)
Spatial organisation of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ.
Development
103
,
155
169
Lyons
K. M.
,
Pelton
R. W.
,
Lyons
B. L. M.
(
1990
)
Organogenesis and pattern formation in the mouse: RNA distribuiton patterns suggest a role for Bone Morphogenetic Protein-2A (BMP-2A).
Development
109
,
833
844
Mackenzie
A.
,
Leeming
G. L.
,
Jowett
A. K.
,
Fergusin
M. W. J.
,
Sharpe
P. T.
(
1991
).
The homeobox gene Hox-7.1 has specific regional and temporal expression patterns during early murine craniofacial embryogenesis, especially tooth development in vivo and in vitro.
Development
111
,
269
285
Mahmood
R.
,
Bresnick
J.
,
Hornbruch
A.
,
Mahony
C.
,
Morton
N.
,
Colquhoun
K.
,
Martin
P.
,
Lumsden
A.
,
Dickson
C.
,
Mason
I.
(
1995
)
A role for Fgf-8 in the initiation and maintenance of vertebrate limb bud outgrowth.
Curr. Biol
5
,
797
806
McGuinness
T.
,
Porteus
M. H.
,
Smiga
S.
,
Bulfone
A.
,
Kingsley
C.
,
Qiu
M.
,
Liu
J.K.
,
Long
J. E.
,
Xu
D.
,
Rubenstein
J. L. R.
(
1996
)
Sequence, orgAnisation and transcription of the Dlx-1 and Dlx-2 locus.
Genomics
35
,
473
485
Ng
L. J.
,
Wheatley
S.
,
Muscat
G. E. O.
,
Conway Campbell
J.
,
Bowles
J.
,
Wright
E.
,
Bell
D. M.
,
Tam
P. P. L.
,
Cheah
K. S. E.
,
Koopman
P.
(
1997
)
SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse.
Dev. Biol
183
,
108
121
Noden
D. M.
(
1983
)
The role of the neural crest in patterning of avian cranial skeletal, connective and muscle tissues.
Dev. Biol
96
,
144
165
Özcelick
T.
,
Porteus
M. H.
,
Rubenstein
J. L. R.
,
Francke
U.
(
1992
)
DLX2 (TES1), a homeobox gene of the Distal-less family, assigned toconserved regions on human and mouse chromosomes 2.
Genomics
13
,
1157
1161
Qiu
M.
,
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 second branchial arch derivatives and abnormal differentiation in the forebrain.
Genes Dev
9
,
2523
2538
Rijli
F. M.
,
Mark
M.
,
Lakkaraju
S.
,
Dierich
A.
,
Dolle
P.
,
Chambon
P.
(
1993
)
A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene.
Cell
75
,
1333
1349
Robinson
G. W.
,
Mahon
K. A.
(
1994
)
Differential and overlapping expression domains of Dlx-2 and Dlx-3 suggest distinct roles for Distal-less homeobox genes in craniofacial development.
Mech. Dev
48
,
199
215
Satokata
I.
,
Maas
R.
(
1994
)
Msx-1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development.
Nature Gen
6
,
348
356
Saxen
L.
(
1966
)
The effect of tetracycline on osteogenesis i n vitro.
J. Exp. Zool
162
,
269
294
Sharpe
P. T.
(
1995
)
Homeobox genes and orofacial development.
Conn. Tiss. Res
32
,
17
25
Simeone
A.
,
Acampora
D.
,
Pannese
M.
,
D'Esposito
M.
,
Stornaiuolo
A.
,
Gulisano
M.
,
Mallamaci
A.
,
Kastury
K.
,
Druck
T.
,
Huebner
K.
,
Boncinelli
E.
(
1994
)
Cloning and characterisation of two members of the vertebrate Dlx gene family.
Proc. Natl. Acad. Sci USA
91
,
2250
2254
Thesleff
I.
,
Vaahtokari
A.
,
Partanen
A.-M.
(
1995
)
Common molecular mechanisms regulating the development of teeth and other organs.
Int. J. Dev. Biol
39
,
35
50
Tissier-Seta
J.-P.
,
Mucchielli
M.-L.
,
Mark
M.
,
Mattei
M.-G.
,
Goridis
C.
,
Bruney
J.-F.
(
1995
)
Barx1, a new mouse homeodomain transcription factor expressed in craniofacial ectomesenchyme and the stomach.
Mech. Dev
51
,
3
15
Trowel
O. A.
(
1959
)
The culture of mature organs in a synthetic medium.
Exp. Cell Res
16
,
118
147
Vainio
S.
,
Karavanova
I.
,
Jowett
A.
,
Thesleff
I.
(
1993
)
Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development.
Cell
75
,
45
58
van Genderen
C.
,
Okamura
R. M.
,
Farinas
I.
,
Quo
R. G.
,
Parslow
T. G.
,
Bruhn
L.
,
Grosschedl
R.
(
1994
)
Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in Lef-1 deficient mice.
Genes Dev
8
,
2691
2703
Wright
E.
,
Hargrave
M. R.
,
Christiansen
J.
,
Cooper
L.
,
Kun
J.
,
Evans
T.
,
Gangadharan
U.
,
Greenfield
A.
,
Koopman
P.
(
1995
)
The Sry -related gene Sox9 is expressed during chondrogenesis in mouse embryos.
Nature Gen
9
,
15
20
This content is only available via PDF.