In Drosophila, the trithorax-group and the Polycomb-group genes are necessary to maintain the expression of the homeobox genes in the appropriate segments. Loss-of-function mutations in those groups of genes lead to misexpression of the homeotic genes resulting in segmental homeotic transformations. Recently, mouse homologues of the Polycomb-group genes were identified including M33, the murine counterpart of Polycomb. In this report, M33 was targeted in mice by homologous recombination in embryonic stem (ES) cells to assess its function during development. Homozygous M33 (−/−) mice show greatly retarded growth, homeotic transformations of the axial skeleton, sternal and limb malformations and a failure to expand in vitro of several cell types including lymphocytes and fibroblasts. In addition, M33 null mutant mice show an aggravation of the skeletal malformations when treated to RA at embryonic day 7.5, leading to the hypothesis that, during development, the M33 gene might play a role in defining access to retinoic acid response elements localised in the regulatory regions of several Hox genes.

REFERENCES

Alkema
M. J.
,
van der Lugt
N. M. T.
,
Bobeldijk
R. C.
,
Berns
A.
,
vanLohuizen
M.
(
1995
)
Transformation of axial skeleton due to overexpression of bmi-1 in transgenic mice.
Nature
374
,
724
727
Akasaka
T.
,
Kanno
M.
,
Balling
R.
,
Mieza
M. A.
,
Taniguchi
M.
,
Koseki
H.
(
1996
)
A role for mel-18, a Polycomb group-related vertebrate gene, during the anteroposterior specification of the axial skeleton.
Development
122
,
1513
1522
Brunk
B. P.
,
Martin
E. C.
,
Adler
P. N.
(
1991
)
Drosophila genes posterior sex combs and suppressor two of zeste encode proteins with homology to the murine bmi-1 oncogene.
Nature
353
,
351
353
Care
A.
,
Testa
U.
,
Bassani
A.
,
Tritarelli
E.
,
Montesoro
E.
,
Samoggia
P.
,
Cianetti
L.
,
Peschle
C.
(
1994
)
Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes.
Mol. Cell. Biol
14
,
4872
4877
Cohen
J. J.
,
Duke
R. C.
(
1984
)
Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death.
J. Immunol
132
,
38
42
Condie
B. G.
,
Capecchi
M. R.
(
1993
)
. Mice homozygous for a targeted disruption of Hox d-3 (Hox −4.1) exhibit anterior transformations of the first and second cervical vertebrae, the atlas and the axis.
Development
119
,
579
595
Condie
B. G.
,
Capecchi
M. R.
(
1994
)
Mice with targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 reveal synergistic interactions.
Nature
370
,
304
306
Conlon
R. A.
,
Rossant
J.
(
1994
)
Exogenous retinoic acid rapidly induces anterior ectopic expression of murine Hox −2 genes in vivo.
Development
116
,
357
368
DeCamillis
M.
,
Cheng
N.
,
Pierre
D.
,
Brock
H. W.
(
1992
)
The polyhomeotic gene of Drosophila encodes a chromatin protein that shares polytene chromosome-binding sites with Polycomb.
Genes Dev
6
,
223
232
Dolle
P.
,
Izpisua-Belmonte
J. C.
,
Falkenstein
H.
,
Renucci
A.
,
Duboule
D.
(
1989
)
Coordinate expression of the murine Hox-5 complex homoeobox-containing genes during limb pattern formation.
Nature
342
,
767
772
Gaunt
S. J.
,
Sharpe
P. T.
,
Duboule
D.
(
1988
)
Spatially restricted domains of homeo-gene transcripts in mouse embryos: relation to a segmented body plan.
Development
104
,
169
179
Hobert
O.
,
Sures
I.
,
Ciossek
T.
,
Fuchs
M.
,
Ullrich
A.
(
1996
)
Isolation and developmental expression analysis of ENX-1, a novel mouse Polycomb group gene.
Mech. Dev
55
,
171
184
Ingham
P. W.
(
1988
)
The molecular genetics of embryonic pattern formation in Drosophila.
Nature
335
,
25
33
Jurgens
G.
(
1985
)
A group of genes controlling the spatial expression of the bithorax complex in Drosophila.
Nature
316
,
153
155
Kessel
M.
,
Gruss
P.
(
1991
)
Homeotic transformation of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid.
Cell
67
,
89
104
Kessel
M.
,
Balling
R.
,
Gruss
P.
(
1990
)
. Variations of cervical vertebrae after expression of a Hox-1.1 transgene in mice.
Cell
61
,
301
308
Krumlauf
R.
(
1994
)
Hox genes in vertebrate development.
Cell
78
,
191
201
Langston
A. W.
,
Gudas
L. J.
(
1992
)
. Identification of a retinoic acid responsive enhancer 3of the murine homeobox gene Hox-1.6. Mech.
Dev
38
,
217
227
Le Mouellic
H.
,
Lallemand
Y.
,
Brulet
P.
(
1992
)
. Homeosis in the mouse induced by a null mutation in the Hox −3.1 gene.
Cell
69
,
251
264
Lufkin
T.
,
Mark
M.
,
Hart
C. P.
,
Dolle
P.
,
LeMeur
M.
,
Chambon
P.
(
1992
)
Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene.
Nature
359
,
835
841
McCall
K.
,
Bender
W.
(
1996
)
Probes of chromatin accessibility in the Drosophila bithorax complex respond differently to Polycomb-mediated repression.
EMBO J
15
,
569
580
McGinnis
W.
,
Krumlauf
R.
(
1992
)
Homeobox genes and axial patterning.
Cell
68
,
283
302
Messmer
S.
,
Franke
A.
,
Paro
R.
(
1992
)
Analysis of the functional role of the Polycomb chromo domain in Drosophila melanogaster.
Genes Dev
6
,
1241
1254
Muller
J.
,
Gaunt
S.
,
Lawrence
P.
(
1995
)
Function of the Polycomb protein is conserved in mice and flies.
Development
121
,
2847
2852
Paro
R.
(
1990
)
Imprinting a determined state into the chromatin of Drosophila.
Trends Genet
6
,
416
421
Pearce
J. H.
,
Singh
P. B.
,
Gaunt
S. J.
(
1992
)
The mouse has a Polycomb -like chromobox gene.
Development
114
,
921
929
Perkins
A.
,
Kongsuwan
K.
,
Visvader
J.
,
Adams
J. M.
,
Cory
S.
(
1990
)
Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia.
Proc. Natl. Acad. Sci. USA
87
,
8398
8402
Popperl
H.
,
Featherstone
M. S.
(
1993
)
. Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene.Mol. Cell.
Biol
13
,
257
265
Ramirez-Solis
R.
,
Zheng
H.
,
Whiting
J.
,
Krumlauf
R.
,
Bradley
A.
(
1993
)
. Hoxb-4(Hox2.6) mutant mice show homeotic transformation of a cervical vertebra and defects in the closure of the sternal rudiments.
Cell
73
,
279
294
Reijnen
M. J.
,
Hamer
K. M.
,
den Blaauwen
J. L.
,
Lambrechts
C.
,
Schoneveld
I.
,
van Driel
R.
,
Otte
A. P.
(
1995
)
Polycomb and bmi-1 homologs are expressed in overlapping patterns in Xenopus embryos and are able to interact with each other.
Mech. Dev
53
,
35
46
Sauvageau
G.
,
Lansdorp
P. M.
,
Eaves
C. J.
,
Hogge
D. E.
,
Dragowska
W. H.
,
Reid
D. S.
,
Largman
C.
,
Lawrence
J. H.
,
Humphries
K. R.
(
1994
)
Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells.
Proc. Natl. Acad. Sci. USA
91
,
12223
12227
Sordino
P.
,
van der Hoeven
F.
,
Duboule
D.
(
1995
)
Hox gene expression in teleost fins and the origin of vertebrate digits.
Nature
375
,
678
681
Tagawa
M.
,
Sakamoto
T.
,
Shigemoto
K.
,
Matsubara
H.
,
Tamura
Y.
,
Ito
T.
,
Nakamura
I.
,
Okitsu
A.
,
Imai
K.
,
Taniguchi
M.
(
1990
)
Expression of novel DNA-binding protein with zinc finger structure in various tumor cells.
J. Biol. Chem
265
,
20021
20026
Tarakhovsky
A.
,
Turner
M.
,
Schaal
S.
,
Mee
P. J.
,
Duddy
L. P.
,
Rajewsky
K.
,
Tybulewicz
V. L.
(
1995
)
Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav.
Nature
374
,
467
470
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
van der Lugt
N. M. T.
, et al. 
(
1994
)
Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene.
Genes Dev
8
,
757
769
van der Lugt
N. M. T.
,
Alkema
M.
,
Berns
A.
,
Deschamps
J.
(
1996
)
The Polycomb -group homolog Bmi-1 is a regulator of murine Hox gene expression.
Mech. Dev
58
,
153
164
van Lohuizen
M.
,
Frasch
M.
,
Wientjens
E.
,
Berns
A.
(
1991
)
Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2.
Nature
353
,
353
355
Wedeen
C.
,
Harding
K.
,
Levine
M.
(
1986
)
Spatial regulation of Antennapedia and Bithorax gene expression by the Polycomb locus of Drosophila.
Cell
44
,
739
748
Yu
B. D.
,
Hess
J. L.
,
Horning
S. E.
,
Brown
G. A.
,
Korsmeyer
S. J.
(
1995
)
Altered Hox expression and segmental identity in Mll-mutant mice.
Nature
378
,
505
508
Zink
B.
,
Engström
Y.
,
Gehring
W. J.
,
Paro
R.
(
1991
)
Direct interaction of the Polycomb protein with Antennapedia regulatory sequences in polytene chromosomes of Drosophila melanogaster.
EMBO J
10
,
153
162
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