Genetic interactions and dosage effects of Polycomb group genes in mice

In Drosophila and mouse, Polycomb group genes are involved in the maintenance of homeotic gene expression patterns throughout development. Here we report the skeletal phenotypes of compound mutants for two Polycomb group genes bmi1 and M33. We show that mice deficient for both bmi1 and M33 present stronger homeotic transformations of the axial skeleton as compared to each single Polycomb group mutant, indicating strong dosage interactions between those two genes. These skeletal transformations are accompanied with an enhanced shift of the anterior limit of expression of several Hox genes in the somitic mesoderm. Our results demonstrate that in mice the Polycomb group genes act in synergy to control the nested expression pattern of some Hox genes in somitic mesodermal tissues during development.

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Molecular characterisation of the Polycomblike gene of Drosophila melanogaster, a trans-acting negative regulator of homeotic gene expression

Development ◽

10.1242/dev.120.9.2629 ◽

1994 ◽

Vol 120 (9) ◽

pp. 2629-2636 ◽

Cited By ~ 19

Author(s):

A. Lonie ◽

R. D'Andrea ◽

R. Paro ◽

R. Saint

Keyword(s):

Gene Expression ◽

Drosophila Melanogaster ◽

Polycomb Group ◽

Negative Regulator ◽

Homeotic Gene ◽

Homeotic Genes ◽

Molecular Characterisation ◽

Polycomb Group Proteins ◽

Polycomb Group Genes ◽

Homeotic Gene Expression

The Polycomblike gene of Drosophila melanogaster, a member of the Polycomb Group of genes, is required for the correct spatial expression of the homeotic genes of the Antennapaedia and Bithorax Complexes. Mutations in Polycomb Group genes result in ectopic homeotic gene expression, indicating that Polycomb Group proteins maintain the transcriptional repression of specific homeotic genes in specific tissues during development. We report here the isolation and molecular characterisation of the Polycomblike gene. The Polycomblike transcript encodes an 857 amino acid protein with no significant homology to other proteins. Antibodies raised against the product of this open reading frame were used to show that the Polycomblike protein is found in all nuclei during embryonic development. Antibody staining also revealed that the Polycomblike protein is found on larval salivary gland polytene chromosomes at about 100 specific loci, the same loci to which the Polycomb and polyhomeotic proteins, two other Polycomb Group proteins, are found. These data add further support for a model in which Polycomb Group proteins form multimeric protein complexes at specific chromosomal loci to repress transcription at those loci.

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Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice

Development ◽

10.1242/dev.124.3.721 ◽

1997 ◽

Vol 124 (3) ◽

pp. 721-729 ◽

Cited By ~ 22

Author(s):

N. Core ◽

S. Bel ◽

S.J. Gaunt ◽

M. Aurrand-Lions ◽

J. Pearce ◽

...

Keyword(s):

Cellular Proliferation ◽

Hox Genes ◽

Es Cells ◽

Embryonic Stem ◽

Axial Skeleton ◽

Polycomb Group ◽

Homeotic Genes ◽

Loss Of Function ◽

Polycomb Group Genes

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.

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Su(z)12, a novelDrosophilaPolycomb group gene that is conserved in vertebrates and plants

Development ◽

10.1242/dev.128.17.3371 ◽

2001 ◽

Vol 128 (17) ◽

pp. 3371-3379 ◽

Cited By ~ 8

Author(s):

Anna Birve ◽

Aditya K. Sengupta ◽

Dirk Beuchle ◽

Jan Larsson ◽

James A. Kennison ◽

...

Keyword(s):

Hox Genes ◽

Position Effect ◽

Polycomb Group ◽

Homeotic Gene ◽

Homeotic Genes ◽

Position Effect Variegation ◽

Regulatory Machinery ◽

Effect Variegation ◽

Arabidopsis Proteins ◽

Homeotic Gene Expression

In both Drosophila and vertebrates, spatially restricted expression of HOX genes is controlled by the Polycomb group (PcG) repressors. Here we characterize a novel Drosophila PcG gene, Suppressor of zeste 12 (Su(z)12). Su(z)12 mutants exhibit very strong homeotic transformations and Su(z)12 function is required throughout development to maintain the repressed state of HOX genes. Unlike most other PcG mutations, Su(z)12 mutations are strong suppressors of position-effect variegation (PEV), suggesting that Su(z)12 also functions in heterochromatin-mediated repression. Furthermore, Su(z)12 function is required for germ cell development. The Su(z)12 protein is highly conserved in vertebrates and is related to the Arabidopsis proteins EMF2, FIS2 and VRN2. Notably, EMF2 is a repressor of floral homeotic genes. These results suggest that at least some of the regulatory machinery that controls homeotic gene expression is conserved between animals and plants.

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Involvement of the Polycomb-group geneRing1Bin the specification of the anterior-posterior axis in mice

Development ◽

10.1242/dev.129.18.4171 ◽

2002 ◽

Vol 129 (18) ◽

pp. 4171-4183 ◽

Cited By ~ 3

Author(s):

Maki Suzuki ◽

Yoko Mizutani-Koseki ◽

Yu-ichi Fujimura ◽

Hiro Miyagishima ◽

Tomomi Kaneko ◽

...

Keyword(s):

Transcriptional Repression ◽

Hox Genes ◽

Protein Complexes ◽

Mouse Genome Informatics ◽

Axial Skeleton ◽

Polycomb Group ◽

Polycomb Group Protein ◽

Chromosomal Dna ◽

Polycomb Group Genes ◽

Group Protein

The products of the Polycomb group of genes form complexes that maintain the state of transcriptional repression of several genes with relevance to development and in cell proliferation. We have identified Ring1B, the product of the Ring1B gene (Rnf2 – Mouse Genome Informatics), by means of its interaction with the Polycomb group protein Mel18. We describe biochemical and genetic studies directed to understand the biological role of Ring1B. Immunoprecipitation studies indicate that Ring1B form part of protein complexes containing the products of other Polycomb group genes, such as Rae28/Mph1 and M33, and that this complexes associate to chromosomal DNA. We have generated a mouse line bearing a hypomorphic Ring1B allele, which shows posterior homeotic transformations of the axial skeleton and a mild derepression of some Hox genes (Hoxb4, Hoxb6 and Hoxb8) in cells anterior to their normal boundaries of expression in the mesodermal compartment. By contrast, the overexpression of Ring1B in chick embryos results in the repression of Hoxb9 expression in the neural tube. These results, together with the genetic interactions observed in compound Ring1B/Mel18 mutant mice, are consistent with a role for Ring1B in the regulation of Hox gene expression by Polycomb group complexes.

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Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice

Development ◽

10.1242/dev.127.23.5093 ◽

2000 ◽

Vol 127 (23) ◽

pp. 5093-5100 ◽

Cited By ~ 6

Author(s):

M. del Mar Lorente ◽

C. Marcos-Gutierrez ◽

C. Perez ◽

J. Schoorlemmer ◽

A. Ramirez ◽

...

Keyword(s):

Gene Expression ◽

Hox Genes ◽

Gene Dosage ◽

Expression Patterns ◽

Ectopic Expression ◽

Axial Skeleton ◽

Polycomb Group ◽

Genetic Evidence ◽

Molecular Evidence ◽

Group Function

The products of the Polycomb group (PcG) of genes act as transcriptional repressors involved in the maintenance of homeotic gene expression patterns throughout development, from flies to mice. Biochemical and molecular evidence suggests that the mouse Ring1A gene is a member of the PcG of genes. However, genetic evidence is needed to establish PcG function for Ring1A, since contrary to all other murine PcG genes, there is no known Drosophila PcG gene encoding a homolog of the Ring1A protein. To study Ring1A function we have generated a mouse line lacking Ring1A and mouse lines overexpressing Ring1A. Both Ring1A(−/−)and Ring1A(+/−) mice show anterior transformations and other abnormalities of the axial skeleton, which indicates an unusual sensitivity of axial skeleton patterning to Ring1A gene dosage. Ectopic expression of Ring1A also results in dose-dependent anterior transformations of vertebral identity, many of which, interestingly, are shared by Ring1A(−/−) mice. In contrast, the alterations of Hox gene expression observed in both type of mutant mice are subtle and involve a reduced number of Hox genes. Taken together, these results provide genetic evidence for a PcG function of the mouse Ring1A gene.

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Genetic interactions and dosage effects of Polycomb group genes of Drosophila

MGG Molecular & General Genetics ◽

10.1007/bf00288601 ◽

1995 ◽

Vol 246 (3) ◽

pp. 291-300 ◽

Cited By ~ 38

Author(s):

Roderick B. Campbell ◽

Donald A. R. Sinclair ◽

Mitchell Couling ◽

Hugh W. Brock

Keyword(s):

Polycomb Group ◽

Genetic Interactions ◽

Polycomb Group Genes ◽

Dosage Effects

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Enhancer of Polycomb Is a Suppressor of Position-Effect Variegation in Drosophila melanogaster

Genetics ◽

10.1093/genetics/148.1.211 ◽

1998 ◽

Vol 148 (1) ◽

pp. 211-220

Author(s):

Donald A R Sinclair ◽

Nigel J Clegg ◽

Jennifer Antonchuk ◽

Thomas A Milne ◽

Kryn Stankunas ◽

...

Keyword(s):

Sequence Similarity ◽

Position Effect ◽

Polycomb Group ◽

P Element ◽

Homeotic Gene ◽

Position Effect Variegation ◽

Negative Regulators ◽

Recombination Mapping ◽

Effect Variegation ◽

Homeotic Gene Expression

Abstract Polycomb group (PcG) genes of Drosophila are negative regulators of homeotic gene expression required for maintenance of determination. Sequence similarity between Polycomb and Su(var)205 led to the suggestion that PcG genes and modifiers of position-effect variegation (PEV) might function analogously in the establishment of chromatin structure. If PcG proteins participate directly in the same process that leads to PEV, PcG mutations should suppress PEV. We show that mutations in E(Pc), an unusual member of the PcG, suppress PEV of four variegating rearrangements: In(l)wm4, BSV, T(2;3)SbV, and In(2R)bwVDe2. Using reversion of a P element insertion, deficiency mapping, and recombination mapping as criteria, homeotic effects and suppression of PEV associated with E(Pc) co-map. Asx is an enhancer of PEV, whereas nine other PcG loci do not affect PEV. These results support the conclusion that there are fewer similarities between PcG genes and modifiers of PEV than previously supposed. However, E(Pc) appears to be an important link between the two groups. We discuss why Asx might act as an enhancer of PEV.

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Trithorax regulates multiple homeotic genes in the bithorax and Antennapedia complexes and exerts different tissue-specific, parasegment-specific and promoter-specific effects on each

Development ◽

10.1242/dev.117.1.119 ◽

1993 ◽

Vol 117 (1) ◽

pp. 119-134 ◽

Cited By ~ 16

Author(s):

T.R. Breen ◽

P.J. Harte

Keyword(s):

Gene Expression ◽

Expression Patterns ◽

The Body ◽

Homeotic Gene ◽

Homeotic Genes ◽

Sex Combs Reduced ◽

Tissue Specific ◽

Specific Effects ◽

Normal Expression ◽

Homeotic Gene Expression

The trithorax (trx) gene is required for normal development of the body plan in Drosophila embryos and adults. Mutations in trx cause homeotic transformations throughout the body. Genetic studies suggest that trx encodes a positive regulatory factor required throughout development for normal expression of multiple homeotic genes of the bithorax and Antennapedia complexes (BX-C and ANT-C). To determine how trx influences homeotic gene expression, we examined the expression of the BX-C genes Ultrabithorax, abdominal-A, Abdominal-B and the ANT-C genes Antennapedia, Sex combs reduced and Deformed in trx embryos. We show that trx does indeed exert its effects by positively regulating homeotic gene expression and that its effects on expression of individual homeotic genes are complex: each of the BX-C and ANT-C genes examined exhibits different tissue-specific, parasegment-specific and promoter-specific reductions in their expression. This implies that each of these genes have different requirements for trx in different spatial contexts in order to achieve normal expression levels, presumably depending on the promoters involved and the other regulatory factors bound at each of their multiple tissue- and parasegment-specific cis-regulatory sites in different regions of the embryo. These results also imply that those components of homeotic gene expression patterns for which trx is dispensable, require other factors, possibly those encoded by other trithorax-like genes.

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Mice doubly deficient for the Polycomb Group genes Mel18 and Bmi1 reveal synergy and requirement for maintenance but not initiation of Hox gene expression

Development ◽

10.1242/dev.128.9.1587 ◽

2001 ◽

Vol 128 (9) ◽

pp. 1587-1597 ◽

Cited By ~ 8

Author(s):

T. Akasaka ◽

M. van Lohuizen ◽

N. van der Lugt ◽

Y. Mizutani-Koseki ◽

M. Kanno ◽

...

Keyword(s):

Gene Expression ◽

Target Genes ◽

Subsequent Development ◽

Axial Skeleton ◽

Polycomb Group ◽

Gene Products ◽

Hox Gene ◽

Hox Cluster ◽

Polycomb Group Genes ◽

Mediate Cell

Polycomb group genes were identified as a conserved group of genes whose products are required in multimeric complexes to maintain spatially restricted expression of Hox cluster genes. Unlike in Drosophila, in mammals Polycomb group (PcG) genes are represented as highly related gene pairs, indicative of duplication during metazoan evolution. Mel18 and Bmi1 are mammalian homologs of Drosophila Posterior sex combs. Mice deficient for Mel18 or Bmi1 exhibit similar posterior transformations of the axial skeleton and display severe immune deficiency, suggesting that their gene products act on overlapping pathways/target genes. However unique phenotypes upon loss of either Mel18 or Bmi1 are also observed. We show using embryos doubly deficient for Mel18 and Bmi1 that Mel18 and Bmi1 act in synergy and in a dose-dependent and cell type-specific manner to repress Hox cluster genes and mediate cell survival of embryos during development. In addition, we demonstrate that Mel18 and Bmi1, although essential for maintenance of the appropriate expression domains of Hox cluster genes, are not required for the initial establishment of Hox gene expression. Furthermore, we show an unexpected requirement for Mel18 and Bmi1 gene products to maintain stable expression of Hox cluster genes in regions caudal to the prospective anterior expression boundaries during subsequent development.

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Functional cooperation between the non-paralogous genes Hoxa-10 and Hoxd-11 in the developing forelimb and axial skeleton

Development ◽

10.1242/dev.122.2.449 ◽

1996 ◽

Vol 122 (2) ◽

pp. 449-460 ◽

Cited By ~ 13

Author(s):

B. Favier ◽

F.M. Rijli ◽

C. Fromental-Ramain ◽

V. Fraulob ◽

P. Chambon ◽

...

Keyword(s):

Hox Genes ◽

Expression Patterns ◽

Axial Skeleton ◽

Proximal Region ◽

Mutant Mice ◽

Phenotypic Traits ◽

Femoral Trochlea ◽

Preferential Expression ◽

Caudal Vertebrae ◽

Compound Mutation

The Abdominal B-related Hoxa-10 gene displays similar expression patterns in the differentiating forelimbs and hindlimbs of the mouse, with preferential expression around the humeral and femoral cartilages and more diffuse expression in distal regions. We found that a targeted disruption of Hoxa-10 has almost no effect in the forelimbs, while it affects the proximal hindlimb skeleton. The alterations were located along the dorsolateral side of the femur (labium laterale), with an enlargement and distal shift of the third trochanter, a misshapen lateral knee sesamoid, a supernumerary ‘ligament’ connecting these structures and an occasional duplication of the femoral trochlea. Some Hoxa-10−/− mutant mice developed severe degenerative alterations of the knee articulation upon ageing. Viable Hoxa-10/Hoxd-11 double mutant mice were produced by genetic intercrosses. The compound mutation resulted in synergistic forelimb phenotypic alterations, consisting of: (i) an exacerbation of Hoxd-11−/− phenotypic traits in the carpal and digital region, e.g. more pronounced truncations of the ulna styloid, pyramidal and pisiform bones and of some metacarpal and phalangeal bones and (ii) marked alterations in a more proximal region which is nearly unaffected in Hoxd-11−/− single mutants; the entire radius and ulna were truncated and thickened, with deformations of the ulna proximal extremity. Thus, functional redundancy can occur even between non-paralogous Abdominal B-related Hox genes. The double Hoxa-10/Hoxd-11 mutation also conferred full penetrance to the sacral and caudal vertebrae transformations which are approximately 50% penetrant in Hoxd-11−/− single mutants, revealing that functional cooperation can also occur between non-paralogous Hox gene products in axial skeleton patterning.

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