Beadex

DEVELOPMENTAL BIOLOGY

To determine the expression pattern of Beadex, in situ hybridization was carried out using Beadex cDNA as a probe. In third instar wing imaginal discs, Beadex is expressed at high levels in the dorsal compartment and at lower levels in the ventral compartment. Beadex also is expressed in the leg and eye discs. In the embryo, Beadex is expressed in the brain and in a subset of cells in the developing central nervous system. The presence of Beadex in many different structures suggests that perhaps dLMO serves multiple functions during development (Zeng, 1998).

Effects of Mutation or Deletion

A model system for the identification of presumptive overproducing mutations from among visible dominant mutations in D. melanogaster is described. An overproducing mutation is expected if a dominant mutation is readily reverted by gene deletion and if gene deletions suppress the expression of the original dominant mutation in flies heterozygous for the deletion. The Beadex mutations are shown to satisfy these requirements, since Bx dominant mutations are reverted by an induced deletion, and are also suppressed in trans by such a deletion. In addition, all 13 mutations recovered as Bx reversions or suppressors are associated with recessive held up (hdp) mutations. It is suggested that hdp functions as a Bx deletion, and may therefore represent the structural gene that is cis-regulated by the overproducing Bx mutations (Lifschytz, 1979).

Recombinant lambda phage clones were isolated spanning 49 kilobases of DNA containing the Beadex and heldup-a loci of Drosophila melanogaster. These cloned DNAs were used to analyze the structures of eight dominant mutant alleles of the Beadex locus that showed increased gene activity. A region, only 700 base pairs in length, is altered in each of these mutants. Six of the mutations have DNA insertions within this segment. Most of these insertions resemble retrovirus-like transposable elements. In one case (Beadex2) the inserted sequences are homologous to the gypsy transposon family. The other two Beadex alleles were induced by hybrid dysgenesis and suffer deletions that include at least part of the 700-base-pair segment. These deletions appear to have resulted from imprecise excision or deletion of a nearby P element found in the wild-type parental strain. Analysis of one heldup-a allele (heldup-aD30r) indicates that a similar P element-mediated event is responsible for this lesion. In this mutant, deletion of sequences no more than 1,600 base pairs from the Beadex locus accompanies the loss of heldup-a function. The deleted sequences in heldup-aD30r include the entire 700-base-pair segment within which at least part of the Beadex locus resides, yet these flies have no Beadex phenotype. This indicates that a functional heldup-a gene is necessary for expression of the Beadex phenotype. Together, these results suggest that the Beadex functional domain is contained within a short segment of DNA near the heldup-a gene and support the hypothesis that the Beadex locus functions as a cis-acting negative regulatory element for the heldup-a gene (Mattox, 1984).

Dlmo (LIM-like) resides in polytene band 17C1-2, where Beadex (Bx) and heldup-a (hdp-a) mutations map. Bx mutations disrupt the 3'UTR of Dlmo, and thereby abrogate the putative negative control elements. This results in overexpression of Dlmo, which causes the wing scalloping that is typical of Bx mutants. The erect wing phenotype of hdp-a results from disruption of the coding region of Dlmo. This provides molecular grounds for the suppression of the Bx phenotype by hdp-a mutations. Phenotypic interaction is demonstrated between the LMO gene Dlmo, the LIM homeodomain gene apterous, and the Chip gene, which encodes a homolog of the vertebrate LIM-interacting protein NLI/Ldb1. It is proposed that by analogy to their vertebrate counterparts, these proteins form a DNA-binding complex that regulates wing development (Shoresh, 1998).

The process of wing patterning involves precise molecular mechanisms to establish an organizing center at the dorsal-ventral boundary, which functions to direct the development of the Drosophila wing. Misexpression of LIM-like (dLMO or Beadex), a Drosophila LIM-only protein, in specific patterns in the developing wing imaginal disc, disrupts the dorsal-ventral (D-V) boundary and causes errors in wing patterning. When dLMO is misexpressed along the anterior-posterior boundary, extra wing outgrowth occurs, similar to the phenotype seen when mutant clones lacking Apterous, a LIM homeodomain protein known to be essential for normal D-V patterning of the wing, are made in the wing disc. When dLMO is misexpressed along the D-V boundary in third instar larvae, loss of the wing margin is observed. This phenotype is very similar to the phenotype of Beadex, a long-studied dominant mutation that disrupts the dLMO transcript in the 3' untranslated region (Zeng, 1998).

Adult wings of homozygous Bx¹ flies show severe scalloping of the wing margin and transformation of dorsal to ventral fate in the alula at the posterior margin of the wing. The abnormalities in Bx wings resemble those produced by reducing ap function. Consistent with the suggestion that Bx mutants reduce Ap function, genetic interaction is observed between Bx and ap, fng, and chip mutants. Flies heterozygous for Bx¹ and a wild-type copy of the gene show mild notching. The severity of this weak Bx¹ phenotype can be enhanced by simultaneously removing one copy of the ap gene, by removing one copy of fng, or by removing one copy of chip, a gene proposed to act as a cofactor for Ap. The strong Bx¹ phenotype can be completely suppressed by increasing the level of ap in dorsal cells. Increasing the level of fng expression also suppresses the wing margin defects but causes other defects in the internal organization of the wing. Taken together, these genetic interactions suggest that the defects caused by overexpressing Bx are due to reduced Ap activity (Milan, 1998).

Bx loss-of-function mutants have been described previously under the name heldup (hdp) because of the abnormal posture of the wings. Unfortunately, the original hdp mutants are no longer available. To study the normal function of dLMO in wing development new mutants were generated by imprecise excision of the MS1096 P element. MS1096 is inserted in the second intron of the Bx-dLMO transcription unit and produces a weak phenotype consisting of venation defects. New Bx^hdp mutants were recovered in P-element excision screens on the basis of their adult wing phenotypes. The wings of the new Bx^hdp mutants are reduced in size and show abnormalities in vein pattern. In addition, the wing posture is abnormal, as described for the original hdp mutants (Milan, 1998).

hdp mutants behave as dominant suppressors of the Bx gain-of-function phenotype. The MS1096 excision mutants completely suppress the Bx phenotype in heterozygous females, suggesting that they are loss-of-function mutants. This was confirmed by examining dLMO protein, which is expressed at much reduced levels in wing discs of the excision mutant hdpR26 (Milan, 1998).

To ask whether the wing abnormalities caused by reducing dLMO levels might be due to an effect on Ap activity, the effects of the Bx^hdp excision mutants were examined on Ap target gene expression. In early third-instar fng-lacZ and Serrate (Ser) are expressed evenly throughout the dorsal compartment of the wing disc and are thought to be regulated by Ap. In Bx^hdp mutant discs, the size of the dorsal compartment is considerably reduced, consistent with the small wing phenotype. fng-lacZ expression is not affected in Bx^hdp discs. Ser expression is elevated in the dorsal compartment and does not resolve normally into stripes along the DV boundary and wing veins. Ser expression in the ventral compartment appears normal. The stripes of Ser expression along the DV boundary and wing veins are both dorsal and ventral and are under different regulation than the early dorsal-specific domain. The abnormal pattern of Ser in the dorsal compartment of the Bx^hdp may be due to superimposition of the early and late expression patterns. It is suggested that this reflects a failure to down-regulate Ap activity as the disc matures. To ask whether elevated Ser levels might contribute to the defects observed in Bx^hdp mutant wings, Ser was overexpressed in the dorsal compartment of an otherwise wild-type disc using ap-gal4 to direct UAS-Ser expression. The resulting wings are small and show thickened veins but do not show the abnormalities in vein pattern observed in the Bx^hdp mutant wings. Overexpression of fng using ap-gal4 in a wild-type background produces no phenotype. These observations suggest that Ser overexpression contributes to the abnormalities observed in Bx^hdp mutant wings but that there are likely to be additional factors. Thus, both gain-of-function and loss-of-function Bx mutant phenotypes can be attributed to abnormal regulation of Ap activity. It is concluded that Ap induces dLMO expression in the wing disc and that dLMO then functions as part of a feedback system to regulate the level of Ap activity (Milan, 1998).

Misexpression of Beadex at the D-V boundary disrupts margin formation and mimics the Beadex phenotype. To test the effect of misexpression of Beadex along the boundary between the dorsal and ventral compartments of the wing disc, Serrate-Gal4 (Ser-G4), which drives expression in the developing wing margin during third instar, was used. Wing margin formation in third instar wing discs was assessed by using wg-lacZ and Cut as markers for the developing wing margin. The margin is discontinuous in discs misexpressing Beadex along the D-V boundary. This disruption of margin formation results in wing scalloping that resembles the Bx phenotype. Misexpression of Beadex along the A-P boundary leads to ectopic margin formation and extra wing outgrowth. ptc-G4 was used to drive misexpression of dLMO along the A-P boundary. A gap in wg-lacZ staining appears in the third instar wing disc where Beadex misexpression intersects the D-V boundary. Additionally, an ectopic wg-lacZ stripe appears along the posterior edge of the ptc-G4 expression domain in the dorsal compartment, perpendicular to the endogenous wing margin. Double-staining for myc-tagged UAS-dLMO and wg-lacZ reveals that wg-lacZ is being expressed in cells both in the Beadex expression domain and in the adjacent cell, similar to wg expression in both the dorsal and ventral cells of the endogenous wing margin. Ct is also expressed along the posterior edge of the Beadex misexpression domain. These markers signify the formation of an ectopic wing margin in the dorsal compartment. Outgrowth organized by this ectopic margin leads to extra wing formation from the dorsal wing blade (Zeng, 1998).

The genetically defined Bx locus corresponds to the 3'UTR of dLMO. Insertion of a P element or a retrotransposon in the 3'UTR of Beadex can result in a dominant wing scalloping phenotype similar to that caused by removal of most or all the AT-rich elements (AREs) and Bearded-like boxes in the 3'UTR. It was surmised that the insertions into the 3'UTR of Bearded (by retrotransposons or P elements or by deletion of parts of the 3'UTR of Bearded) similarly abrogate the negative regulatory effect of the ARE and Brd-like motifs. Consequently, the level of the Beadex transcript in the Bx alleles examined is two- to four-fold higher than that of the wild type, as expected if the ARE and Brd-like boxes have an RNA-destabilizing effect (Shoresh, 1998).

Recessive hdp-a mutations have been genetically mapped to close proximity (0.0045 map units) to the Bx mutations, in the direction opposite from the centromere. Furthermore, hdp-a mutations have been reported to suppress in one dose the dominant wing scalloping of Bx mutations either in cis or in trans. Based on these observations, the hypermorphic nature of Bx mutations has been proposed to result from overexpression of a nearby structural gene, possibly hdp-a. Although all previously existing hdp-a alleles have been lost, new hdp-a mutants were generated in two ways, and both groups recapitulate the two characteristics of the previous alleles, namely erect wings and suppression of the dominant wing scalloping of Bx mutants. Molecular analysis has been carried out on one of them, hdp-a^32-4-14, demonstrating that it has a deletion of a major part of the coding region of Dlmo, including part of the second LIM domain, suggesting that hdp-a corresponds to loss-of-function of Dlmo. Comparison to the map of Beadex suggests that the deletion in hdp-a^D30r has removed part of the coding region of the gene. Loss of function of Dlmo could be also caused by mutations disrupting the promoter region of the gene (Shoresh, 1998).

Dorsoventral axis formation in the Drosophila wing depends on the activity of the selector gene apterous. Although selector genes are usually thought of as binary developmental switches, Apterous activity is found to be negatively regulated during wing development by its target gene dLMO. Apterous-dependent expression of Serrate and fringe in dorsal cells leads to the restricted activation of Notch along the dorsoventral compartment boundary. Evidence is presented that the ability of cells to participate in this Apterous-dependent cell-interaction is under spatial and temporal control. Apterous-dependent expression of dLMO causes downregulation of Serrate and fringe and allows expression of Delta in dorsal cells. This limits the time window during which dorsoventral cell interactions can lead to localized activation of Notch and induction of the dorsoventral organizer. Overactivation of Apterous in the absence of dLMO leads to overexpression of Serrate, reduced expression of Delta and concomitant defects in differentiation and cell survival in the wing primordium. Thus, downregulation of Apterous activity is needed to allow normal wing development (Milan, 2000).

Removing Apterous activity at different stages of wing development shows that Ap is needed throughout larval stages to confer dorsal cell identity, but its role in Notch activation along the DV boundary is temporally and spatially modulated. This can be explained in terms of changes in Serrate and fringe expression. Some of the changes in Serrate and fringe expression are caused by reducing Ap activity, whereas others are Ap independent. In early second instar wing discs, Ap activity is required in the entire dorsal compartment. Removing Ap activity in mitotic recombination clones at this stage induces Notch activation at the interface between wild-type and mutant cells. This response is independent of the position of the clone within the wing pouch. In early third instar wing discs, Ap-dependent expression of Serrate and fringe is reduced by dLMO. Serrate expression gradually becomes restricted to the region near the DV boundary and, subsequently, by mid-third instar is induced only in cells adjacent to the boundary. The effects of removing Ap activity in clones reflects the gradual retraction of Serrate expression toward the DV boundary. Clones of cells lacking Ap activity induced in early third instar activate the Notch pathway and induce Wg if they are located close to the DV boundary. Clones located more proximally do not show this response. This spatial difference can be overcome by providing Serrate in proximal cells (Milan, 2000).

By mid-third instar, new Ap-independent patterns of Serrate and fringe expression are observed. Serrate is expressed on both sides of the DV boundary by the activity of Wg, and fringe is expressed in four quadrants flanking the DV and AP compartment boundaries. Maintenance of Notch activation along the DV boundary is now under control of a feedback loop between Wg and Serrate and Delta. Ap is no longer required for Notch activation at the DV boundary and removing Ap activity no longer leads to activation of the Notch pathway. In the absence of dLMO, Ap activity remains at high early levels as development proceeds. Serrate and fringe expression remain high throughout the dorsal compartment and fail to undergo normal modulation. In addition, Delta is not expressed in dorsal cells. Ap-dependent repression of Delta at early stages is needed to prevent ectopic activation of Notch in dorsal cells, which are inherently Delta-sensitive due to the activity of Fringe. Some of the defects observed in dLMO mutant wings are correlated with excess Serrate activity and insufficient Delta activity. In addition, abnormally high levels of cell death in the dorsal compartment of the dLMO mutant wing disc are due to excess Ap activity and this leads to overall reduction in the size of the wing. These findings indicate the need to downregulate Ap activity to allow normal wing development. However, Ap activity continues to be required for dorsal cell fate specification and for proper adhesion of D and V wing surfaces. Thus it is proposed that different target genes may be controlled at different levels of Ap activity. Serrate, fringe and Delta may be regulated by a higher level of Ap activity than the target genes involved in surface apposition or fate specification. Temporal changes in the level of Ap activity may be required to modulate activity of different genes at different times to allow normal wing development (Milan, 2000).

Drosophila LIM-only is a positive regulator of transcription during thoracic bristle development

The Drosophila LIM-only (Lmo) protein DLMO functions as a negative regulator of transcription during development of the fly wing. This study reports a novel role of Dlmo as a positive regulator of transcription during the development of thoracic sensory bristles. New dlmo mutants, which lack some thoracic dorsocentral (DC) bristles, were isolated. This phenotype is typical of malfunction of a thoracic multiprotein transcription complex, composed of Chip, Pannier (Pnr), Achaete (Ac), and Daughterless (Da). Genetic interactions reveal that dlmo synergizes with pnr and ac to promote the development of thoracic DC bristles. Moreover, loss-of-function of dlmo reduces the expression of a reporter target gene of this complex in vivo. Using the GAL4-UAS system it was also shown that dlmo is spatially expressed where this complex is known to be active. Glutathione-S-transferase (GST)-pulldown assays showed that Dlmo can physically bind Chip and Pnr through either of the two LIM domains of Dlmo, suggesting that Dlmo might function as part of this transcription complex in vivo. It is proposed that Dlmo exerts its positive effect on DC bristle development by serving as a bridging molecule between components of the thoracic transcription complex (Zenvirt, 2008).

The results presented in this study uncover a novel role of Dlmo in regulation of the development of the thoracic DC bristles. Homozygous, or hemizygous, loss-of-function (dlmo^hdp) mutants lack the anterior pair of the DC bristles. Moreover, these dlmo mutants displayed genetic interactions with mutants in genes known to regulate DC bristle development, such as pnr and ac, to reduce the number of DC bristles. Consistently, overexpression alleles of dlmo (dlmo^Bx) also exhibited genetic interactions with these pnr and ac mutants, resulting in an increased number of bristles. In addition, the finding that overexpression of pnr under the regulation of dlmo-GAL4 affects DC bristle development suggests that dlmo is expressed in the region of the wing disc that gives rise to these bristles (Zenvirt, 2008).

These results suggest a role of Dlmo in positive regulation of transcription. The negative role of Dlmo in modulation of transcription during Drosophila wing development has been well documented. The findings indicate that in another context, namely in regulation of DC bristle development by the Chip, Pnr, Ac and Da (CPAD) complex, Dlmo has another role, as a positive regulator of transcription. Lowering the level of Dlmo (in dlmo^hdp mutants) results in a reduction in the expression of a reporter driven by regulatory sequences of a bona fide target gene of the CPAD transcription complex, suggesting that Dlmo is a positive regulator of CPAD-dependent transcription. While the mechanism by which Dlmo positively regulates transcription in the context of the CPAD complex remains to be elucidated, a first clue to this mechanism may lie in the finding that Dlmo can bind constituent proteins of this complex, including Pnr and Chip, in vitro. Should these interactions also take place in vivo, Dlmo may exert its positive role in transcriptional regulation as a component of the CPAD complex (Zenvirt, 2008).

Insights into the mechanism of positive transcriptional regulation by Dlmo can be gleaned from LMO2, one of the mammalian homologs of Dlmo. LMO2 was demonstrated to participate in a multiprotein transcription complex that contains Ldb1, a GATA factor (GATA-1 or GATA-2), and the bHLH transcription factors TAL1 and E2A, which are homologous, respectively, to the fly components of the CPAD complex, Chip, Pannier, Achaete, and Daughterless. Various lines of evidence indicate that in mammals LMO2 serves as a bridge between components of the complex, and silencing of LMO2 causes disruption of the complex and decreases in the activation of transcription of its target genes, just as does silencing of Ldb1 or Tal1. Similarly to LMO2, Dlmo might serve as a bridge between components of the CPAD complex. LIM domains are protein-interaction modules and could serve Dlmo to bind components of the CPAD complex. This suggestion is supported by the finding that each single LIM domain of Dlmo is capable of binding components of the CPAD complex in vitro, and it agrees with similar reports on other LIM-containing proteins. Notably, a single LIM domain from LMO2 and LMO4 is sufficient to interact with Ldb1 or the related protein CLIM-1a. However, both LIM domains are required for the highest-affinity interactions (Zenvirt, 2008).

This proposed mode of action of Dlmo, as a bridging molecule, which binds a different protein through each one of its LIM domains, predicts that a Dlmo molecule with one defective LIM domain and one intact LIM domain would bind only one protein at a time and not be able to bridge between molecules. Indeed, in the new dlmo mutants, it was found that deletions that span the second zinc finger of the second LIM domain of Dlmo, namely dlmo^hdp48-1 and dlmo^hdp185-1, resulted in dlmo loss-of-function mutations. These mutants display partial loss of thoracic DC bristles along with reduced expression of a target gene of the thoracic transcription complex. Interestingly, the wing size of these mutants is normal, unlike the small wings of mutants with lesions in the 5'-UTR of Dlmo, such as dlmo^hdp58-1, dlmo^hdp67-2, and dlmo^hdpR590. This may suggest that the defective Dlmo protein, which has only a single intact LIM domain, is sufficient for its function in the context of the wing, where Dlmo acts as a negative regulator that binds only one protein (CHIP), but is not sufficient when Dlmo acts as a bridging molecule in the thoracic CPAD transcription complex. Finally, the finding that Dlmo can bind other Dlmo molecules to generate homodimers or multimers might provide Dlmo with a greater flexibility of bridging between distant components of the complex. This possibility remains to be examined (Zenvirt, 2008).

In conclusion, Dlmo appears to have a dual role in regulation of transcription, depending on the context. Such a phenomenon has been documented for other transcription cofactors, whose dual function in transcription regulation varies according to their binding partners, the specific tissue, or the developmental stage. Likewise, these results indicate Dlmo has such a dual role, being a negative regulator with respect to the Ap-Chip complex and a positive regulator in the context of the CPAD complex (Zenvirt, 2008).

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date revised: 25 June 2011

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