groucho

DEVELOPMENTAL BIOLOGY

Embryonic

Maternal expression of groucho is essential during neuroblast and epidermoblast segregation (Schrons, 1992). Long and short transcripts show no detectable difference in expression patterns. Initial expression in blastula [Image] and gastrula stages is ubiquitous. Labeling eventually becomes restricted to the central nervous system, with a marked decrease in ectodermal expression. Notch expression continues high in the ectoderm (Hartley, 1988).

Larval

groucho is expressed in imaginal discs where it serves to repress hedgehog and engrailed in the anterior compartment (de Celis, 1995).

On the mechanism underlying the divergent retinal and bristle defects of M8* (E(spl)D) in Drosophila

Multisite phosphorylation has been implicated in repression by E(spl)M8. It is proposed that these phosphorylations occur in the morphogenetic furrow (MF) to reverse an auto-inhibited state of M8, enabling repression of Atonal during R8 specification. These studies address the paradoxical behavior of M8*, the truncated protein encoded by E(spl)D. It is suggested that differences in N signaling in the bristle versus the eye underlie the antimorphic activity of M8* in N⁺ (ectopic bristles) and hypermorphic activity in N^spl (reduced eye). Ectopic M8* impairs eye development (in N^spl) only during establishment of the atonal feedback loop (anterior to the MF), but is ineffective after this time point. In contrast, a CK2 phosphomimetic M8 lacking Groucho (Gro) binding, M8SDDeltaGro, acts antimorphic in N⁺ and suppresses the eye/R8 and bristle defects of N^spl, as does reduced dosage of E(spl) or CK2. Multisite phosphorylation could serve as a checkpoint to enable a precise onset of repression, and this is bypassed in M8* (Kahali, 2009).

Effects of Mutation or Deletion

groucho is named for a mutant with an increased number of supraorbital bristles (bristles around the eye), reminiscent of the bushy browed Marx brother (Schrons, 1992). Embryos lacking maternally supplied Groucho may lack embryonic epidermis, or exhibit neurogenic phenotypes (Paroush, 1994).

The Drosophila Epidermal growth factor receptor (Egfr) is a key component of a complex signaling pathway that participates in multiple developmental processes. An F1 screen was performed for mutations that cause dominant enhancement of wing vein phenotypes associated with mutations in Egfr. With this screen, mutations were recovered in Hairless (H), vein, groucho (gro), and three apparently novel loci. All of the enhancers of Egfr mutations [E(Egfr)] identified show dominant interactions in transheterozygous combinations with one another and with alleles of N or Su(H), suggesting that they are involved in cross-talk between the N and Egfr signaling pathways. Further examination of the phenotypic interactions between Egfr, H, and gro reveals that reductions in Egfr activity enhances both the bristle loss associated with H mutations, and the bristle hyperplasia and ocellar hypertrophy associated with gro mutations. Double mutant combinations of Egfr and gro hypomorphic alleles leads to the formation of ectopic compound eyes in a dosage sensitive manner. These findings suggest that these E(Egfr)s represent links between the Egfr and Notch signaling pathways, and that Egfr activity can either promote or suppress Notch signaling, depending on its developmental context (Price, 1997).

Genetic interactions between the N and Egfr signaling pathways have been reported previously. There is a mutual enhancement between N gain-of-functions (gof) and Egfr loss-of-functon (lof) mutations and mutual suppression between lof alleles of Delta and Egfr. Egfr gof alleles enhance Notchspl in the eyes and Delta loss-of-function alleles in the wings of double mutant flies. Mutations in Egfr and two other Egfr pathway components (Son of sevenless and pointed) act as enhancers of N signaling in the eye. Mutations in both Hairless and groucho enhance L4 wing vein defects associated with mutations in both Egfr and vein. Egfr. In turn, Egfr mutations enhance the Hairless mutant-associated loss of macrochaetae and microchaetae from the head and thorax; therefore, Egfr and Hairless appear to cooperate in at least two developmental processes. Groucho appears to be required in contexts that appear to be distinct from its function in Notch signaling. Ectopic wing hairs are observed on the wings of Egfr, groucho and rolled;groucho double mutants that are similar to defects seen in hairy mutant flies or groucho/hairy transheterozygotes, and may indicate that Egfr mutations reduce Groucho's activity as a corepressor with Hairy. The spectrum of defects enhanced in Egfr;gro or rolled;groucho double mutants appears to reflect a reduction in most or all aspects of groucho activity. The simplest interpretation of these observations is that both Egfr and Rolled promote the activity of Groucho. Gro and its mammalian homolog, TLE1, are phosphorylated on serine residues and thus may be downstream targets of an Egfr-regulated phosphorylation cascade (Price, 1997 and references).

The Notch receptor triggers a wide range of cell fate choices in higher organisms. In Drosophila, segregation of neural from epidermal lineages results from competition among equivalent cells. These cells express achaete/scute genes, which confer neural potential. During lateral inhibition, a single neural precursor is selected, and neighboring cells are forced to adopt an epidermal fate. Lateral inhibition relies on proteolytic cleavage of Notch induced by the ligand Delta and translocation of the Notch intracellular domain (NICD) to the nuclei of inhibited cells. The activated NICD, interacting with Suppressor of Hairless [Su(H)], stimulates genes of the E(spl) complex, which in turn repress the proneural genes achaete/scute. New alleles of Notch are described that specifically display loss of microchaetae sensory precursors. This phenotype arises from a repression of neural fate, by a Notch signaling distinct from that involved in lateral inhibition. The loss of sensory organs associated with this phenotype results from a constitutive activation of a Deltex-dependent Notch-signaling event. These novel Notch alleles encode truncated receptors lacking the carboxy terminus of the NICD, which is the binding site for the repressor Dishevelled (Dsh). Dsh is known to be involved in crosstalk between Wingless and Notch pathways. These results reveal an antineural activity of Notch distinct from lateral inhibition mediated by Su(H). This activity, mediated by Deltex (Dx), represses neural fate and is antagonized by elements of the Wingless (Wg)-signaling cascade to allow alternative cell fate choices (Raiman, 2001).

In a screen for flies associated with the loss of microchaetae, a number of mutations in Notch were isolated that result in a dominant loss of thoracic microchaetae, which are called N^Mcd, where Mcd stands for microchaetae defective. These mutations are lethal, and, for this reason, their behavior was analyzed in mosaics in which clones of mutant cells are juxtaposed with wild-type territories. In these mosaics, mutant cells are recognized by the use of both bristle and epidermal markers. All mutants behave genetically in a similar manner, the strongest alleles, N^Mcd1 and N^Mcd5 (collectively N^Mcd1/5), were chosen for further analysis. In clones for N^Mcd1 and N^Mcd5, 99% of the microchaetae are absent, whereas macrochaetae are not affected (Raiman, 2001).

Genetic analysis indicates that the dominant effects of the N^Mcd alleles are due to antagonism of the wild-type function of Notch. The mutant phenotype of N^Mcd is enhanced when N⁺ is lowered and is partially suppressed when N⁺ is increased. Thus, these gain-of-function alleles of Notch do not induce an aberrant function of the receptor (neomorphism), but rather produce receptors that are more active on the normal function of Notch. N^Ax alleles exhibit a similar genetic behavior and a similar phenotype to the N^Mcd alleles. However, several differences distinguish N^Ax from N^Mcd. The N^Ax mutant exhibits a variable loss of both thoracic microchaetae and macrochaetae, leading to irregular patterns. In contrast, N^Mcd affects only microchaetae. Furthermore, the remaining microchaetae of the N^Mcd/+ flies are arranged in fewer rows, which are organized in a regular pattern. Finally, N^Ax/+ flies exhibit broader wings with shortened veins. In contrast, the wings of the N^Mcd/+ flies appear as those of wild-type flies. In this study of the N^Mcd alleles, focus was placed on the bristle pattern (Raiman, 2001).

A further demonstration of the specificity of the N^Mcd mutations for microchaetae is seen by analysis of N^Mcd1/5clones with impaired function of either hairy or extramacrochaetae (emc), two negative regulators of ac/sc. Flies lacking hairy or its cofactor groucho (gro) exhibit ectopic microchaetae in the scutellum region of the thorax. In clones mutant for N^Mcd1/5 and lacking gro (N^Mcd1/5 gro^-cells), ectopic microchaetae are absent. In contrast, the N^Ax mutants again behave differently, since, in Ax^59b gro^- cells, ectopic microchaetae form. The ectopic macrochaetae, which develop in emc¹clones, also arise in N^Mcd1/5 emc¹clones, even when their precursors differentiate simultaneously to those of the microchaetae (Raiman, 2001).

In the absence of any component of lateral inhibition, an excess of neural precursors occurs at the expense of epidermis. In Notch^-, Su(H)^-, and Dl^-clones (mosaic animals), the neurogenic phenotype is extreme; all mutant cells adopt the neural fate, and no cells are left to form epidermis. The lack of epidermal mutant cells leads to a wound partially skinned up by wild-type epidermal-surrounding cells. In gro^- and E(spl)^-, as well as in the hypomorphic Dl clones, the neurogenic phenotype is less severe, and such clones can differentiate tufts of densely packed sensory bristles accompanied by few epidermal cells. Furthermore, mutant cells for loss-of-function alleles of Notch have an enhanced capacity to produce an inhibitory signal that forces neighboring wild-type cells to adopt the epidermal fate. This signal is mediated by Delta. Thus, along the borders of N mutant clones, no bristles are formed by wild-type cells (Raiman, 2001).

Alleles of Notch encoding constitutively activated receptors show the opposite phenotype, with wild-type bristles forming at the border of mutant territories that adopt epidermal fate. The phenotype of the N^Mcd mutants resembles that of classic gain-of-function alleles of Notch (among which are the N^Ax alleles) and therefore might result in an activation of the lateral inhibition function. If this were the case, removal of the function of some or all of the mediators of lateral inhibition will abolish the effects of the N^Mcdalleles. To test this, double-mutant clones were made using the loss-of-function mutations Dl^RevF10, Dl^9P39, Df(3R)E(spl)b32.2, gro^E48, and Su(H)^IB115. In this case, double-mutant clones for N^Mcd1,5 and components that mediate lateral inhibition [Delta; E(spl)-C; gro; Su(H)] would be predicted to inactivate lateral signaling; they would be predicted to display the neurogenic phenotypes characterized by the lack of mutant epidermal cells. Surprisingly, in all cases, the double-mutant clones display the N^Mcd1/5 phenotype with mutant epidermis and no microchaetae differentiated. Therefore, N^Mcdcells do not require Dl, Su(H), gro, or the E(spl)-C in order to adopt the epidermal fate. In contrast, neurogenic double-mutant clones are observed using Ax^59bor Ax^SX1and at least with Dl, gro, and E(spl)-C. The N^Mcd Ser and N^Mcd Dl Ser clones display the N^Mcdphenotype, suggesting that the N^Mcdphenotype does not require Serrate, the other ligand of Notch (Raiman, 2001).

The macrochaetae can differentiate normally in clones mutant for N^Mcd. In the absence of lateral signaling (double-mutant clones for N^Mcd1,5 and one of the components of lateral inhibition [Dl; E(spl)-C; gro; Su(H)]), mutant clones would be predicted to display tufts of macrochaetae (the neurogenic phenotype). Macrochaetae differentiating as single bristles are observed rather than as a neurogenic tuft. These results confirm that the N^Mcdmutants affect a function of Notch distinct from lateral inhibition (Raiman, 2001).

Genetic interactions among scribbler, Atrophin and groucho in Drosophila uncover links in transcriptional repression

In eukaryotes, the ability of DNA-binding proteins to act as transcriptional repressors often requires that they recruit accessory proteins, known as corepressors, which provide the activity responsible for silencing transcription. Several of these factors have been identified, including the Groucho (Gro) and Atrophin (Atro) proteins in Drosophila. Strong genetic interactions are seen between gro and Atro and also with mutations in a third gene, scribbler (sbb), which encodes a nuclear protein of unknown function. Mutations in Atro and Sbb have similar phenotypes, including upregulation of the same genes in imaginal discs, which suggests that Sbb cooperates with Atro to provide repressive activity. Comparison of gro and Atro/sbb mutant phenotypes suggests that they do not function together, but instead that they may interact with the same transcription factors, including Engrailed and C15, to provide these proteins with maximal repressive activity (Wehn, 2006; full text of article).

Previous studies demonstrated that Atro acts as a corepressor in Drosophila, the most convincing of these being the demonstration that fusion of Atro to a heterologous DNA-binding domain confers repressive activity to the chimera. Atro has been shown to interact directly with two transcription factors, Even-Skipped (Eve) and Huckebein, and the repressive ability of Eve is compromised in Atro mutants, probably accounting for the loss of en expression in even-numbered parasegments in Atro mutant embryos (Wehn, 2006).

These studies here are consistent with Atro acting as a corepressor since it was shown that several genes, including run, tkv, al, and B, are completely or partially derepressed in Atro mutant clones in imaginal discs, suggesting that transcriptional repressors required to silence these genes recruit Atro. Atro-dependent repression of Bar (B) in the center of the leg disc is very likely due to interaction with the transcription factor C15, which is expressed in the center of the leg and is required for repression of B. Similarly, Atro-dependent repression of al in the posterior of the wing is very likely due to interaction with En, which is expressed in the posterior and required to exclude al from this compartment. At present it is unclear which transcription factors recruit Atro to repress run in the eye or tkv in the wing, although a strong candidate for run would be the Rough homeodomain protein, which is expressed in the same cells, R2 and R5, that exhibit ectopic run expression in Atro mutant clones. Whether Atro can, in fact, bind directly to C15, En, and possibly Rough, needs to be tested biochemically, since previous studies with Eve and Hkb did not identify a possible interaction motif for Atro nor do sequence comparisons among C15, En, Eve, and Hkb suggest a common motif (Wehn, 2006).

The sbb gene encodes a nuclear protein with unknown function. sbb mutations have many different phenotypes affecting multiple tissues. sbb and Atro interact very strongly genetically and that many of the phenotypes of sbb mutants are very similar to those of Atro mutants, including derepession of run, tkv, al, and B in imaginal discs. Thus, Atro is unable to silence these genes in the absence of Sbb, suggesting that it is required for Atro activity either to recruit Atro to transcription factors or possibly to assist binding of these factors to DNA. Since these transcription factors appear to function normally in some respects in the absence of Sbb (or Atro), it appears more likely that Sbb and Atro function together in a corepressor complex (Wehn, 2006).

One problem with the proposal that Atro activity is dependent upon Sbb is that the phenotypes of Atro and sbb mutants are not identical. For example, embryos lacking both maternal and zygotic Atro have a very severe, almost uncharacterizable phenotype, while embryos lacking both maternal and zygotic Sbb have a much less severe phenotype, characterized by a reduced number of abdominal segments, that is similar to that of embryos lacking only maternal Atro. This could be explained if Atro is partially active in the absence of Sbb, or if it is dependent upon Sbb for repression of some genes but not others. Alternatively, the difference between Atro and sbb mutant phenotypes could be related to Atro having functions other than that of a corepressor. It is has been implicated in positive regulation of Hox gene expression, and it also functions in the cytoplasm to control planar cell polarity. This analysis of sbb mutants does not reveal any potential involvement of Hox gene expression or planar cell polarity and, consequently, if Sbb is required only for Atro to act as a corepressor, then it is not surprising that Atro and sbb mutant phenotypes are not identical. Further experiments are required to determine the nature of the Atro dependence on Sbb for transcriptional repression and how direct any interactions might be (Wehn, 2006).

Mutations in sbb and Atro were originally uncovered in a genetic screen for enhancers of al. It is likely that they act as enhancers because they are utilized by the C15 transcription factor to repress genes such as Bar; C15 is expressed in the same cells as Al and it is thought that they bind together to regulate gene expression. Strong genetic interactions were uncovered among sbb, Atro, and en mutations, that could be explained if En also recruits Atro/Sbb (Wehn, 2006).

Curiously, genetic studies also revealed strong interactions among gro, sbb, and Atro. This could be explained if Gro was also required for Atro activity; i.e., all three proteins may form a corepressor complex. However, this appears to be unlikely because, in contrast to the similar phenotypes of sbb and Atro mutants, there are several distinct differences among the phenotypes of gro mutants and those of sbb and Atro mutants. For example, repression of tkv in the anterior of the wing is dependent on both Sbb and Atro but not on Gro, while repression of run in the antennal disc is dependent upon Gro but not upon Atro or Sbb. This suggests that a specific transcription factor recruits Atro/Sbb to repress tkv in the wing and another transcription factor recruits Gro to repress run in the antenna. The identity of these transcription factors remains to be uncovered (Wehn, 2006).

In some cases gro mutants do have a similar phenotype to those of Atro and sbb; this includes partial derepression of al expression in the posterior of the wing and Bar in the center of the leg. This can be explained if C15 (expressed in the center of the leg) and En (expressed in the posterior of the wing) recruit both Gro and Atro/Sbb and if each imparts some but not all the repressive activity to these transcription factors. Consistent with this, both C15 and En possess eh1-type Gro-interaction motifs and previous studies have revealed that En can repress in the absence of Gro. Further biochemical studies are required to determine if C15 and En can indeed recruit Atro (Wehn, 2006).

At present it is unclear whether Atro and Gro provide all the repressive activity to C15 and En; this will await the generation of Atro gro double-mutant clones. sbb gro double-mutant clones have been analyzed and these reveal that some targets of C15 and En are still at least partially repressed, although En activity appears to be somewhat compromised following the simultaneous loss of Sbb and Gro, in comparison to loss of one of these alone. Either Atro has some activity in the absence of Sbb or C15 and En can use mechanisms other than recruitment of Gro and Atro to repress transcription. Many transcription factors have been shown to have the ability to repress by several mechanisms; for example, although Brk recruits both CtBP and Gro, it can repress some genes in the absence of both, using additional repression domains (Wehn, 2006).

Why do C15 and En need to recruit both Gro and Atro? En can repress some genes completely in the absence of either Gro or Atro, for example, ci and dpp in the wing. However, for repression of al, the activity of En is clearly reduced in the absence of either, indicating that it needs to recruit both to completely repress this gene. This would suggest a quantitative explanation; i.e., En recruits both Gro and Atro to increase its activity, rather than to allow it to repress specific genes repressed more efficiently by one or the other. This is consistent with the suggestion that both corepressors function via a similar mechanism: both Gro and a vertebrate homolog of Atro have been shown to recruit a histone deacetylase. The recruitment of both may decrease histone acetylation to a level that cannot be achieved with either alone (Wehn, 2006).

Apidianakis, Y., et al. (2001). Groucho mediates a Ci-independent mechanism of hedgehog repression in the anterior wing pouch. Development 128: 4361-4370. 11684670

Aronson, B. D., et al. (1997). Groucho-dependent and -independent repression activities of Runt domain proteins. Mol. Cell. Biol. 17(9): 5581-5587.

Bae, Y.-K., et al. (2003). A homeobox gene, pnx, is involved in the formation of posterior neurons in zebrafish. Development 130: 1853-1865. 12642490

Barolo, S. and Posakony, J. W. (2002a). Three habits of highly effective signaling pathways: Principles of transcriptional control by developmental cell signaling. Genes Dev. 16: 1167-1181. 12023297

Barolo, S., et al. (2002b). Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. Genes Dev. 16: 1964-1976. 12154126

Benítez, E., Bray, S. J., Rodriguez, I. and Guerrero, I. (2009). Lines is required for normal operation of Wingless, Hedgehog and Notch pathways during wing development. Development 136(7): 1211-21. PubMed Citation: 19270177

Bianchi-Frias, D., et al. (2004). Hairy transcriptional repression targets and cofactor recruitment in Drosophila. PLoS Biol. 2(7): E178. 15252443

Brantjes, H., Roose, J., van De Wetering, M. and Clevers, H. (2001). All Tcf HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Res. 29(7): 1410-9. 11266540

Broihier, H. T. and Skeath, J. B. (2002). Drosophila homeodomain protein dHb9 directs neuronal fate via crossrepressive and cell-nonautonomous mechanisms Neuron 35: 39-50. 12123607

Brou, C., et al. (1994). Inhibition of the DNA-binding activity of Drosophila Suppressor of Hairless and of its human homolog, KBF2/RBP-Jkappa, by direct protein-protein interaction with Drosophila Hairless. Genes Dev. 8: 2491-2503. 7958912

Calvo, D. et al. (2001). A POP-1 repressor complex restricts inappropriate cell type-specific gene transcription during Caenorhabditis elegans embryogenesis. EMBO J. 20: 7197-7208. 11742996

Canon, J. and Banerjee, U. (2003). In vivo analysis of a developmental circuit for direct transcriptional activation and repression in the same cell by a Runx protein. Genes Dev. 17: 838-843. 12670867

Castro, B., Barolo, S., Bailey, A. M. and Posakony, J. W. (2005). Lateral inhibition in proneural clusters: cis-regulatory logic and default repression by Suppressor of Hairless. Development. 132(15): 3333-44. 15975935

Cavallo, R. A., et al. (1998). Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 395(6702): 604-8.

Chanut, F., Luk, A. and Heberlein, U. (2000). A screen for dominant modifiers of ro^Dom, a mutation that disrupts morphogenetic furrow progression in Drosophila, identifies groucho and hairless as regulators of atonal expression Genetics 156(3): 1203-17. 11063695

Chen, G., Nguyen, P. H. and Courey, A. J. (1998). A role for Groucho tetramerization in transcriptional repression. Mol. Cell. Biol. 18(12): 7259-7268.

Chen, G., et al. (1999). A functional interaction between the histone deacetylase Rpd3 and the corepressor Groucho in Drosophila development. Genes Dev. 13: 2218-2230.

Choi, C. Y. et al. (1999). The homeodomain transcription factor NK-4 acts as either a transcriptional activator or repressor and interacts with the p300 coactivator and the groucho corepressor. J. Biol. Chem. 274: 31543-31552.

Choi, C. Y., Kim, Y. H., Kim, Y. O., Park, S. J., Kim, E. A., Riemenschneider, W., Gajewski, K., Schulz, R. A. and Kim, Y. (2005). Phosphorylation by the DHIPK2 protein kinase modulates the corepressor activity of Groucho. J. Biol. Chem. 280: 21427-21436. PubMed Citation: 15802274

Collins, R. T. and Treisman, J. E. (2000). Osa-containing Brahma chromatin remodeling complexes are required for the repression of Wingless target genes. Genes Dev. 14: 3140-3152. 11124806

Copley, R. R. (2005). The EH1 motif in metazoan transcription factors. BMC Genomics 6: 169. 16309560

Cowden, J. and Levine, M. (2003). Ventral dominance governs sequential patterns of gene expression across the dorsal-ventral axis of the neuroectoderm in the Drosophila embryo. Dev. Biol. 262: 335-349. 14550796

Dasen, J. S., et al. (2001). Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev. 15: 3193-3207. 11731482

Dawson, S. R., et al.(1995). Specificity for the hairy/enhancer of split basic helix-loop-helix (bHLH) proteins maps outside the bHLH domain and suggests two separable modes of transcriptional repression. Mol Cell Biol 15: 6923-6931

de Celis, J. F. and Rulz-Gomez, M. (1995). groucho and hedgehog regulate engrailed expression in the anterior compartment of the Drosophila wing. Development 121: 3467-76

Dehni, G., et al. (1995). TLE expression correlates with mouse embryonic segmentation, neurogenesis, and epithelial determination. Mech. Dev. 53: 369-381

Dorfman, R., et al. (2002). Elbow and Noc define a family of zinc finger proteins controlling morphogenesis of specific tracheal branches. Development 129: 3585-3596. 12117809

Doyle, M. J., Loomis, Z. L. and Sussel, L. (2007). Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet. Development 134(3): 515-23. Medline abstract: 17202186

Dubnicoff, T., Valentine, S. A., Chen, G., Shi, T., Lengyel, J. A., Paroush, Z. and Courey, A. J. (1997). Conversion of Dorsal from an activator to a repressor by the global corepressor Groucho. Genes Dev. 11(22): 2952-2957.

Ducker, C. E. and Simpson, R. T. (2000). The organized chromatin domain of the repressed yeast a cell-specific gene STE6 contains two molecules of the corepressor Tup1p per nucleosome. Embo J. 19: 400-409

Eberhard, D., et al. (2000). Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J. 19: 2292-2303. 10811620

Edmondson, D.G., Smith, M. M. and Roth, S. Y. (1996). Repression domain of the yeast global repressor Tup1 interacts directly with histones H3 and H4. Genes & Dev. 10: 1247-1259.

Fisher, A. L., Ohsako, S. and Caudy, M. (1996).The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain. Mol. Cell. Biol. 16: 2670-2677

Fisher, A. L. and M. Caudy. 1998. Groucho proteins: Transcriptional corepressors for specific subsets of DNA-binding transcription factors in vertebrates and invertebrates. Genes Dev. 12: 1931-1940.

Flores-Saaib, R. D., Jia, S. and Courey, A. J., (2001). Activation and repression by the C-terminal domain of Dorsal. Development 128: 1869-1879. 11311166

Giagtzoglou, N., et al. (2003). Two modes of recruitment of E(spl) repressors onto target genes. Development 130: 259-270. 12466194

Goldstein, R. E., et al. (1999). Huckebein repressor activity in Drosophila terminal patterning is mediated by Groucho. Development 126: 3747-3755. 10433905

Goldstein, R. E., et al. (2005). An eh1-like motif in Odd-skipped mediates recruitment of Groucho and repression in vivo. Mol. Cell. Biol. 25(24): 10711-20. 16314497

Grbavec, D. and Stifani, S. (1996). Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. Biochem. Biophys. Res. Commun. 223: 701-705

Grbavec, D., et al. (1998). Transducin-like Enhancer of split 2, a mammalian homologue of Drosophila Groucho, acts as a transcriptional repressor, interacts with Hairy/Enhancer of split proteins, and is expressed during neuronal development. Eur. J. Biochem. 258(2): 339-49.

Grbavec, D., et al. (1999). Groucho/transducin-like enhancer of split (TLE) family members interact with the yeast transcriptional co-repressor SSN6 and mammalian SSN6-related proteins: implications for evolutionary conservation of transcription repression mechanisms. Biochem J. 337 (Pt 1): 13-7.

Gutjahr, T., et al. (1995). The Polycomb-group gene, extra sex combs, encodes a nuclear member of the WD-40 repeat family. EMBO J 14: 4296-4306

Hader, T., et al. (1999). Receptor tyrosine kinase signaling regulates different modes of Groucho-dependent control of Dorsal. Curr. Biol. 10: 51-54.

Hasson, P., Egoz, N., Winkler, C., Volohonsky, G., Jia, S., Dinur, T., Volk, T., Courey, A. J. and Paroush, Z. (2005). EGFR signaling attenuates Groucho-dependent repression to antagonize Notch transcriptional output. Nat. Genet. 37: 101-105. 15592470

Hartley, D.A., Preiss, A. and Artavanis-Tsakonas, S. (1988). A deduced gene product from the Drosophila neurogenic locus, Enhancer of split, shows homology to mammalian G-protein beta subunit. Cell 55: 785-795

Hasson, P., et al. (2001). Brinker requires two corepressors for maximal and versatile repression in Dpp signalling. EMBO J. 20: 5725-5736. 11598015

Huang, L., Zhang, W. and Roth, S. Y. (1997). Amino termini of histones H3 and H4 are required for a1-alpha2 repression in yeast. Mol. Cell. Biol. 17(11): 6555-6562.

Husain, J., et al. (1996). Affinity for the nuclear compartment and expression during cell differentiation implicate phosphorylated Groucho/TLE1 forms of higher molecular mass in nuclear functions. Biochem. J. 317: 523-531

Imai, Y., et al. (1998). TLE, the human homolog of groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation. Biochem. Biophys. Res. Commun. 252(3): 582-9.

Jennings, B. H., et al. (2006). Molecular recognition of transcriptional repressor motifs by the WD Domain of the Groucho/TLE corepressor. Mol. Cell 22: 645-655. 16762837

Jennings, B. H., Wainwright, S. M. and Ish-Horowicz, D. (2008). Differential in vivo requirements for oligomerization during Groucho-mediated repression. EMBO Rep. 9(1): 76-83. PubMed Citation: 18034187

Jennings, B. H., Wainwright, S. M. and Ish-Horowicz, D. (2008). Differential in vivo requirements for oligomerization during Groucho-mediated repression. EMBO Rep. 9(1): 76-83. PubMed Citation: 18034187

Jimenez, G., Paroush, Z. and Ish-Horowicz, D. (1997). Groucho acts as a corepressor for a subset of negative regulators, including hairy and engrailed. Genes Dev. 11(22): 3072-3082.

Jimenez, G., Verrijzer, C. P. and Ish-Horowicz, D. (1999). A conserved motif in Goosecoid mediates Groucho-dependent repression in Drosophila embryos. Mol. Cell. Biol. 19(3): 2080-7.

Jimenez, G., et al. (2000). Relief of gene repression by torso RTK signaling: role of capicua in Drosophila terminal and dorsoventral patterning. Genes Dev. 14(2): 224-31.

Ju, B. G., et al. (2004). Activating the PARP-1 sensor component of the Groucho/ TLE1 corepressor complex mediates a CaMKinase II-dependent neurogenic gene activation pathway. Cell 119: 815-829. 15607978

Kahali, B., Bose, A., Karandikar, U., Bishop, C. P. and Bidwai, A. (2009). On the mechanism underlying the divergent retinal and bristle defects of M8* (E(spl)D) in Drosophila. Genesis 47(7): 456-68. PubMed Citation: 19415625

Kawamura, A., et al. (2005). Groucho-associated transcriptional repressor ripply1 is required for proper transition from the presomitic mesoderm to somites. Dev. Cell 9(6): 735-44. 16326386

Kobayashi, M., et al. (2001a). Groucho augments the repression of multiple Even skipped target genes in establishing parasegment boundaries. Development 128(10): 1805-1815. 11311161

Kobayashi, M., et al. (2001b). The homeobox protein Six3 interacts with the groucho corepressor and acts as a transcriptional repressor in eye and forebrain formation. Dev. Bio. 232: 315-326

Koop, K. E., MacDonald, L. M. and Lobe, C. G. (1996). Transcripts of Grg4, a murine groucho-related gene, are detected in tissues adjacent to other murine neurogenic gene homologs during embryonic development. Mech. Dev. 59: 73-87

Lee, W., Andrews, B. C., Faust, M., Walldorf, U. and Verheyen, E. M. (2009). Hipk is an essential protein that promotes Notch signal transduction in the Drosophila eye by inhibition of the global co-repressor Groucho. Dev. Biol. 325(1): 263-72. PubMed Citation: 19013449

Levanon, D., et al. (1998). Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc. Natl. Acad. Sci. 95(20): 11590-5.

Lickteig, K, M., et al. (2001). Regulation of neurotransmitter vesicles by the homeodomain protein UNC-4 and its transcriptional corepressor UNC-37/Groucho in Caenorhabditis elegans cholinergic motor neurons. J. Neurosci. 21(6): 2001-2014. 11245684

Liotta, D., Han, J., Elgar, S., Garvey, C., Han, Z. and Taylor, M. V. (2007). The Him gene reveals a balance of inputs controlling muscle differentiation in Drosophila. Current Biol. 17: 1409-1413. Medline abstract: 17702578

López-Ríos, J., et al. (2003). Six3 and Six6 activity is modulated by members of the groucho family. Development 130: 185-195. 12441302

Mallo, M., Franco del Amo, F. and Gridley, T. (1993). Cloning and developmental expression of Grg, a mouse gene related to the goucho transcript of the Drosophila Enhance of split complex. Mech. Dev. 42: 67-76.

Mallo, M., et al. (1994). Genomic organization, alternative polyadenylation and chromosomal localization of Grg, a mouse gene related to the groucho transcript of the Drosophila Enhancer of split complex. Genomics 21: 194-201

Mallo, M.., et al. (1995). Protein characterization and targeted disruption of Grg, a mouse gene related to the groucho transcript of the Drosophila Enhancer of split complex. Dev. Dyn. 204: 338-347

Martinez, C. A. and Arnosti. D. N. (2008). Spreading of a corepressor linked to action of long-range repressor hairy. Mol. Cell. Biol. 28(8): 2792-802. PubMed Citation: 18285466

Miyasaka, H., et al. (1993). Molecular cloning and expression of mouse and human cDNA encoding AES and ESG proteins with strong similarity to Drosophila enhancer of split groucho protein. Eur. J. Biochem. 216(1): 343-352.

Muhr, J., et al. (2001). Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell 104: 861-873. 11290324

Nagel, A. C., et al. (2005). Hairless-mediated repression of Notch target genes requires the combined activity of Groucho and CtBP corepressors. Mol. Cell. Biol. 25(23): 10433-41. 16287856

Nakayama, H., et al. (1997). Developmental restriction of Mash-2 expression in trophoblast correlates with potential activation of the notch-2 pathway. Dev. Genet. 21(1): 21-30.

Nibu, Y., Zhang, H. and Levine, M. (2001). Local action of long-range repressors in the Drosophila embryo. EMBO J. 20: 2246-2253. 11331590

Palaparti, A., Baratz, A. and Stifani, S. (1997). The Groucho/Transducin-like enhancer of split transcriptional repressors interact with the genetically defined amino-terminal silencing domain of histone H3. J. Biol. Chem. 272(42): 26604-26610.

Paroush, Z., et al. (1994). groucho is required for Drosophila neurogenesis, segmentation and sex determination and interacts directly with Hairy-related bHLH proteins. Cell 79: 805-815

Paroush, Z., Wainwright, S. M. and Ish-Horowicz, D. (1997). Torso signalling regulates terminal patterning in Drosophila by antagonising Groucho-mediated repression. Development 124(19): 3827-3834.

Peden, E., et al. (2007). Control of sex-specific apoptosis in C. elegans by the BarH homeodomain protein CEH-30 and the transcriptional repressor UNC-37/Groucho. Genes Dev 21: 3195-3207. PubMed citation: 18056429

Pflugrad, A., et al. (1997). The Groucho-like transcription factor UNC-37 functions with the neural specificity gene unc-4 to govern motor neuron identity in C. elegans. Development 124: 1699-1709.

Phippen, T. M., et al. (2000). Drosophila C-terminal binding protein functions as a context-dependent transcriptional co-factor and interferes with both mad and groucho transcriptional repression. J. Biol. Chem. 275(48): 37628-37. 10973955

Pinto, M., and Lobe, C. G. (1996). Products of the grg (Groucho-related gene) family can dimerize through the amino-terminal Q domain. J. Biol. Chem. 271: 33026-31

Price, J. V., et al. (1997). Dominant enhancers of Egfr in Drosophila melanogaster: genetic links between the Notch and Egfr signaling pathways. Genetics 147(3): 1139-1153. PubMed Citation: 9383058

Protzer, C. E., Wech, I. and Nagel, A. C. (2008). Hairless induces cell death by downregulation of EGFR signalling activity. J. Cell Sci. 121(Pt 19): 3167-76. PubMed Citation: 18765565

Ramain, P., et al. (2001). Novel Notch alleles reveal a Deltex-dependent pathway repressing neural fate. Cur. Bio. 11: 1729-1738. 11719214

Ren, B., et al. (1999). PRDI-BF1/Blimp-1 repression is mediated by corepressors of the groucho family of proteins. Genes Dev. 13(1): 125-37.

Roose, J., et al. (1998). The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 395(6702): 608-12.

Runko, A. P. Sagerström, C. G. (2003). Nlz belongs to a family of zinc-finger-containing repressors and controls segmental gene expression in the zebrafish hindbrain. Dev. Biol. 262: 254-267. 14550789

Schrons, H. Knust, E., and Campos-Ortega, J. A. (1992). The Enhancer of split complex and adjacent genes in the 96F region of Drosophila melanogaster are required for segregation of neural and epidermal progenitor cells . Genetics 132: 481-503

Sathe, S. S. and Harte, P. J. (1995a). The Drosophila extra sex combs protein contains WD motifs essential for its function as a repressor of homeotic genes. Mech Dev 52: 77-87

Schmidt, C. J. and Sladek, T. E. (1993). A rat homolog of the Drosophila enhancer of split (groucho) locus lacking WD-40 repeats. J Biol Chem 268: 25681-6

Sekiya, T. and Zaret, K. S. (2007). Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo. Mol. Cell 28: 291-303. PubMed Citation: 17964267

Sekiya, T. and Zaret, K. S. (2007). Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo. Mol. Cell 28: 291-303. PubMed Citation: 17964267

Sugiyama, S., Funahashi, J.-i. and Nakamura, H. (2000). Antagonizing activity of chick Grg4 against tectum-organizing activity. Dev. Bio. 221: 168-180.

Sugiyama, S. and Nakamura, H. (2003). The role of Grg4 in tectal laminar formation. Development 130: 451-462. 12490552

Tabuchi, K., Yoshikawa, S., Yuasa, Y., Sawamoto, K. and H. Okano. (1998). A novel Drosophila paired-like homeobox gene related to Caenorhabditis elegans unc-4 is expressed in subsets of postmitotic neurons and epidermal cells. Neurosci. Lett. 257: 49-52.

Takke, C. and Campos-Ortega, J. A. (1999). her1, a zebrafish pair-rule like gene, acts downstream of notch signalling to control somite development. Development 126, 3005-3014.

Tata, F. and Hartley, D. A. (1993). The role of the enhancer of split complex during cell fate determination in Drosophila. Dev Suppl: 139-148

Tetsuka, T., et al. (2000). Inhibition of nuclear factor-kappaB-mediated transcription by association with the amino-terminal enhancer of split, a groucho-related protein lacking WD40 repeats. J. Biol. Chem. 275(6): 4383-90.

Tolkunova, E. N., et al. (1998). Two distinct types of repression domain in Engrailed: One interacts with the Groucho corepressor and is preferentially active on integrated target genes. Mol. Cell. Biol. 18(5): 2804-2814.

Tulin, A., Stewart, D. and Spradling, A. C. (2002). The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev. 16(16): 2108-19. 12183365

Tulin, A. and Spradling, A. (2003). Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science 299: 560-562. 12543974

Uhler, J., Zhang, H., Syu, L. J. and Mellerick, D. M. (2007). The Nk-2 box of the Drosophila homeodomain protein, Vnd, contributes to its repression activity in a Groucho-dependent manner. Mech. Dev. 124(1): 1-10. Medline abstract: 17070676

Von Ohlen, T., Syu, L. J. and Mellerick, D. M. (2007). Conserved properties of the Drosophila homeodomain protein, Ind. Mech. Dev. 124(11-12): 925-3417900877

Von Stetina, S. E., et al. (2007). UNC-4 represses CEH-12/HB9 to specify synaptic inputs to VA motor neurons in C. elegans. Genes Dev. 21: 332-346. Medline abstract: 17289921

Wang, J. C., et al. (2000). Transducin-like enhancer of split proteins, the human homologs of Drosophila groucho, interact with hepatic nuclear factor 3beta. J. Biol. Chem. 275(24): 18418-23. 10748198

Wehn, A. and Campbell, G. (2006). Genetic interactions among scribbler, Atrophin and groucho in Drosophila uncover links in transcriptional repression. Genetics 173(2): 849-61. 16624911

Wang, X., et al. (2007). Transcription elongation controls cell fate specification in the Drosophila embryo. Genes Dev. 21: 1031-1036

Wheeler, J. C., et al. (2002). Distinct in vivo requirements for establishment versus maintenance of transcriptional repression. Nat. Genet. 32(1): 206-10. 12145660

Winnier, A. R., et al. (1999). UNC-4/UNC-37-dependent repression of motor neuron-specific genes controls synaptic choice in Caenorhabditis elegans. Genes Dev. 13: 2774-2786.

Wubeck, C. and Campos-Ortega, J. A. (1997). Two zebrafish homologues of the Drosophila neurogenic gene groucho and their pattern of transcription during early embryogenesis. Dev. Genes Evol. 207: 156-166

Yao, J., et al. (2000). Disrupted development of the cerebral hemispheres in transgenic mice expressing the mammalian Groucho homologue Transducin-like- Enhancer of split 1 in postmitotic neurons. Mech. Dev. 93: 105-115.

Yao, J., Lai, E. and Stifani, S. (2001). The winged-helix protein Brain Factor 1 interacts with Groucho and Hes proteins to repress transcription. Mol. Cell. Bio. 21: 1962-1972. 11238932

Yarmus, M., et al. (2006). Groucho/transducin-like Enhancer-of-split (TLE)-dependent and -independent transcriptional regulation by Runx3. Proc. Natl. Acad. Sci. 103(19): 7384-9. 16651517

Yu, Z., Syu, L. J. and Mellerick, D. M. (2005). Contextual interactions determine whether the Drosophila homeodomain protein, Vnd, acts as a repressor or activator. Nucleic Acids Res. 33(1): 1-12. Medline abstract: 15640442

Zhang, H. and Levine, M. (1999). Groucho and dCtBP mediate separate pathways of transcriptional repression in the Drosophila embryo. Proc. Natl. Acad. Sci. 96(2): 535-40.

Zhang, H., Levine, M. and Ashe, H. L. (2001). Brinker is a sequence-specific transcriptional repressor in the Drosophila embryo. Genes Dev. Vol. 15: 261-266. 11159907

Zhu, C. C., et al. (2002). Six3-mediated auto repression and eye development requires its interaction with members of the Groucho-related family of co-repressors. Development 129: 2835-2849. 12050133

date revised: 25 October 2009

 

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