C-terminal binding protein
Developmental Northern analysis of wild-type flies using the CtBP two-hybrid insert as a probe shows that three major transcripts (2.5, 2.7 and 4.0 kb) are expressed dynamically throughout all stages of development, whereas an additional 3.5 kb transcript is detected predominantly in adult females and embryos stages. CtBP transcript levels increase both early, during oogenesis and embryogenesis, and later in pre-pupae stages. CtBP expression is detected ubiquitously in the germarium and early oogenic stages and is highly expressed in nurse cells by stage 10. This transcript is dumped into the oocyte and is detected ubiquitously as a maternal transcript in early and cellular blastoderm stage embryos (Poortinga, 1998).
It has been demonstrated that CtBP is essential for proper embryonic segmentation by analyzing embryos lacking maternal CtBP activity. While hairy is probably not the only segmentation gene interacting with CtBP, dose-sensitive genetic interactions exist between CtBP and hairy mutations (Poortinga, 1998).
The P1590 strain carries a homozygous lethal insertion, with the homozygotes dying as pharate adults. When dissected from their pupal cases, CtBP/1590 homozygotes exhibit duplicated and ectopic bristles (macrochaetes) on the notum and scutellum. The P1590 strain also exhibits a strong maternal effect phenotype. It was on the basis of its maternal requirement that the P-1590 allele was identified in a screen for maternal-effect lethals. In this screen, a change of function mutation in an RNA polymerase II subunit (wimp) was used to reduce, but not eliminate, P-1590 maternal contribution. Embryos derived from mothers trans-heterozygous for wimp and the P1590 allele die, and cuticle preparations of these embryos show segmentation defects, ranging from pair-wise fusions of adjacent denticle bands to more widespread denticle fusions (Poortinga, 1998).
Since wimp reduces, but does not eliminate maternal function, loss of CtBP/P1590 function in germline clones was examined using the FLP-DFS technique. The FLP-DFS system incorporates the presence of a dominant female sterile (DFS) mutation, ovoD1, and the FLP-FRT yeast site-specific recombination system to create germline-specific mosaics. A P1590 FRT82B chromosome had been generated previously as part of a screen using the FLP-DFS technique to look for maternal phenotypes in zygotic single P-element-induced mutations. Embryos derived from germline clones generated with this chromosome were reported to have segmentation defects resulting in pair-wise fusions, as well as large holes in the ventral cuticle (Perrimon, 1996). Using this P1590 FRT82B stock, more severe cuticle disruptions have been obtained than previously reported: embryos were consistently observed that are significantly shorter than wild-type, with either 'lawns' of denticles on the ventral cuticle or severely fused or missing denticle bands (Poortinga, 1998).
If the segmentation defects observed in embryos lacking maternal CtBP are due to its interaction with Hairy, disruptions in patterning similar to those found in hairy mutations or loss of maternal Groucho are expected. In particular, the expression of the other primary pair-rule genes are expected to be disrupted and fushi tarazu expression to be derepressed. Consistent with this, Ftz stripes are found to be expanded in embryos lacking maternal CtBP. However, this broad band of expression later resolves into stripe-specific ftz repression, with stripes 2, 4, 5 and 6 predominantly affected. Aberrant expression of the primary pair-rule gene proteins, Eve and Runt, as well as of Hairy itself are also observed. Since the primary pair-rule genes respond directly to gap gene cues, gap gene expression was examined in embryos lacking maternal CtBP. Expression of the three gap genes examined, Hunchback, Krüppel and Knirps, appears normal in these embryos. In addition to its effects on anterior-posterior patterning, embryos lacking maternal CtBP also show disruptions of dorsoventral patterning. Beginning with the expression of the pair-rule genes, a lack of segmentation gene expression is detected on the ventral surface (Poortinga, 1998).
In addition to the disruption of patterning in P1590 germline clones, CtBP/P1590 was examined for genetic interaction with hairy. h mutations result in a range of cuticle phenotypes from loss or fusion of adjacent denticle bands to a fusion of most of the segments ('lawn' phenotype), with the most common phenotype called the classic pair-rule phenotype that results from the loss of alternating segment-wide regions. Larvae homozygous for a strong h allele, h7H, display the extreme 'lawn' phenotype, whereas larvae trans-heterozygous for the h7H allele and a weaker h allele, h12C, display the classic pair-rule phenotype. This h7H/h12C allelic combination was initially used to examine if reducing the CtBP dose maternally would suppress or enhance the intermediate pair-rule phenotype. P1590 was genetically recombined onto a chromosome containing the h7H allele. Reducing the dose of CtBP maternally results in the suppression of the h7H/h12C mutant cuticle phenotype. Likewise, reducing the dose of CtBP maternally in the severe h7H background suppresses the extreme lawn phenotype. No alterations in viability or phenotype of any progeny classes are observed when P1590 is trans-heterozygous with h7H, or when the h7H P1590 recombinant chromosome is crossed to wild-type (Poortinga, 1998).
C-terminal binding protein (CtBP) is an evolutionarily and functionally conserved transcriptional corepressor known to integrate diverse signals to regulate transcription. Drosophila CtBP (dCtBP) regulates tissue specification and segmentation during early embryogenesis. This study investigated the roles of dCtBP during development of the peripheral nervous system (PNS). This study includes a detailed quantitative analysis of how altered dCtBP activity affects the formation of adult mechanosensory bristles. dCtBP loss-of-function was shown to result in a series of phenotypes with the most prevalent being supernumerary bristles. These dCtBP phenotypes are more complex than those caused by Hairless, a known dCtBP-interacting factor that regulates bristle formation. The emergence of additional bristles correlated with the appearance of extra sensory organ precursor (SOP) cells in earlier stages, suggesting that dCtBP may directly or indirectly inhibit SOP cell fates. It was also found that development of a subset of bristles was regulated by dCtBP associated with U-shaped through the PxDLS dCtBP-interacting motif. Furthermore, the double bristle with sockets phenotype induced by dCtBP mutations suggests the involvement of this corepressor in additional molecular pathways independent of both Hairless and U-shaped. It is therefore proposed that dCtBP is part of a gene circuitry that controls the patterning and differentiation of the fly PNS via multiple mechanisms (Stern, 2009).
This study provides evidence that dCtBP is required for different aspects of PNS development. In addition, extensive genetic characterization demonstrates how altered dCtBP activity can influence the formation of the adult dorsal thoracic mechanosensory organs. The data show that overexpression of dCtBP impairs mechanosensory formation. In contrast, reduction of dCtBP activity leads to variable bristle phenotypes, suggesting that dCtBP is likely operating in different molecular complexes. Namely, the mechanisms by which dCtBP regulates cell fate specification within the PNS may involve protein–protein interactions between dCtBP and at least two factors: Ush and possibly H (Stern, 2009).
The data strongly suggest that dCtBP associates with the Ush-Pnr repressor complex through the Ush PxDLS motif to inhibit the expression of achaete and scute in particular PNCs. This model is supported by the following evidence. First, the ush loss-of-function and gain-of-function phenotypes were phenocopied by the corresponding genetic alterations to dCtBP activity. Second, Ush interacts with Pnr and the Ush-Pnr complex inhibits expression of the achaete and scute genes through GATA sites located within the DC enhancer. Third, the additional SOP cells were formed in both the dCtBP and ush mutant imaginal discs. Fourth, both ush and pnr alleles exhibited dominant genetic interactions with dCtBP. Finally, disruption of the PxDLS motif of Ush partially mitigated the effects of ush overexpression on particular bristles (Stern, 2009).
The evolutionarily conserved physical interaction of dCtBP with Ush is essential for the propagation of certain cell lineages, such as blood cells (crystal cells) of the fruit fly, but not for heart development, processes known to be regulated by Ush and the GATA factors, Pnr and Serpent. Surprisingly, the interaction between CtBP and FOG-1 is not required for erythroid development in mice, despite the fact that this interaction was found to be important in tissue culture experiments and in frog embryos. The current results from the ush overexpression assay suggest that Ush may utilize both the PxDLS motif and another repression domain(s) to fully function, since particular bristles are affected by disruption of the PxDLS motif of Ush. A putative corepressor that interacts with the additional repression domain may act additively or cooperatively with dCtBP or function in different tissue/cell-type contexts. In fact, recently other repression domains in Ush, required for repression of the D-mef2 cardiac gene, were identified and these seemed to cooperatively work with the dCtBP-dependent motif. Consistent with this hypothesis, some dCtBP-interacting factors contain multiple repression domains. Knirps (nuclear receptor), Snail (zinc-finger protein), and H all have two repression domains, dCtBP-dependent and -independent, which can function additively in transgenic flies and/or in tissue culture. It has been also demonstrated that H has an additional repression activity independent of Groucho and dCtBP-binding. Krüppel (zinc-finger protein) has two evolutionarily conserved repression domains. The dCtBP-dependent domain is functional in tissue culture and in transgenic embryos, while the other repression domain is only active in tissue culture but not in transgenic embryos, suggesting a cell-type specific effect. Finally, Brinker (a helix-turn-helix protein) contains at least three repression domains (dCtBP-dependent, Groucho-dependent, and the third repression domain) that are important for repression of different target genes (Stern, 2009).
The physical interaction of dCtBP with H is implicated in sensory organ formation, wing formation, and embryonic patterning. H acts as an adaptor protein to bridge the Groucho and dCtBP corepressors to the DNA-binding factor Su(H), to ultimately inhibit Notch target genes. Vertebrate Notch target genes are similarly repressed by a complex consisting of CtBP with RBP-Jkappa (the mammalian counterpart to Su(H)) and the SHARP/CtIP corepressors. This study demonstrates that the bristles that are affected in dCtBP mutants also show defects in H loss-of-function mutants, although the effect of H is stronger than that of dCtBP. H mutations induce two distinct phenotypes associated with loss of bristles; one is the bald phenotype (a complete loss of both sockets and bristles) due to lack of SOP cells, and the other is the double-socket phenotype (also lack of bristles). A similar bald phenotype was observed in dCtBP mutant backgrounds, such as dCtBP RNAi, the dCtBP87De-10/dCtBP03463 transheterozygote, the dCtBP87De-10 clonal backgrounds. Although compared to what is seen in dCtBP mutants, reduction of H activity interferes more uniformly with the formation of all 11 bristles that were analyzed, the bald phenotype further supports previous observations that dCtBP is involved in H-mediated repression. The double-socket phenotype seen in H loss-of-function mutants was never observed in dCtBP mutants. This distinct phenotype suggests that H may play a role independent of dCtBP, possibly by interacting with another corepressor Groucho. Interestingly, the bald phenotype was also induced by overexpression of dCtBP. The mechanism by which overexpression causes the bald phenotype in all regions except the DC region remains unclear, although one simple explanation could be that overproduction of dCtBP may disrupt the stoichiometric balance of the H/dCtBP/Groucho repression complex (Stern, 2009).
The double bristle phenotype observed in dCtBP mutants suggests that dCtBP may be required to execute cell fate decisions within the SOP lineage. A similar phenotype seen in the H gain-of-function background was the result of a socket-to-bristle cell fate transformation. Of note, this phenotype is clearly distinct from the double bristle phenotype observed in dCtBP mutants, which is always associated with a socket(s). This dCtBP phenotype implies that cousin-to-cousin cell fate conversions may be occurring within the sensory organ lineage. This type of cell fate switch could be similar to the conversion of sheath to bristle observed in hamlet mutants. Hamlet is a zinc-finger transcription factor and interestingly contains a PLDLS peptide sequence located between amino acid 747 and 751, identical to the CtBP-interacting motif. Future experiments will address whether dCtBP and Hamlet can physically interact and function together within the same biological process (Stern, 2009).
Based on the results, it is concluded that dCtBP regulates the development of the mechanosensory organs likely via multiple mechanisms. This highlights the centrality of this transcriptional corepressor in integrating multiple inputs to define boundaries and thereby control pattern formation during development (Stern, 2009).
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C-terminal binding protein:
Biological Overview
| Evolutionary Homologs
| Regulation
| Developmental Biology
| Effects of Mutation
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