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PubMed1999

Trithorax- and Polycomb-group response elements within an Ultrabithorax transcription maintenance unit consist of closely situated but separable sequences.

In Drosophila, two classes of genes, the trithorax group and the Polycomb group, are required in concert to maintain gene expression by regulating chromatin structure. We have identified Trithorax protein (TRX) binding elements within the bithorax complex and have found that within the bxd/pbx regulatory region these elements are functionally relevant for normal expression patterns in embryos and confer TRX binding in vivo. TRX was localized to three closely situated sites within a 3-kb chromatin maintenance unit with a modular structure. Results of an in vivo analysis showed that these DNA fragments (each approximately 400 bp) contain both TRX- and Polycomb-group response elements (TREs and PREs) and that in the context of the endogenous Ultrabithorax gene, all of these elements are essential for proper maintenance of expression in embryos. Dissection of one of these maintenance modules showed that TRX- and Polycomb-group responsiveness is conferred by neighboring but separable DNA sequences, suggesting that independent protein complexes are formed at their respective response elements. Furthermore, we have found that the activity of this TRE requires a sequence (approximately 90 bp) which maps to within several tens of base pairs from the closest neighboring PRE and that the PRE activity in one of the elements may require a binding site for PHO, the protein product of the Polycomb-group gene pleiohomeotic. Our results show that long-range maintenance of Ultrabithorax expression requires a complex element composed of cooperating modules, each capable of interacting with both positive and negative chromatin regulators.

Animals↗

PubMed1994

Homeotic gene expression in the locust Schistocerca: an antibody that detects conserved epitopes in Ultrabithorax and abdominal-A proteins.

To investigate what role homeotic genes may play in morphological evolution, we are comparing homeotic gene expression in two very different insects, Drosophila (Diptera) and Schistocerca (Orthoptera). In this paper we describe a monoclonal antibody, FP6.87, that recognizes the products of both the Ultrabithorax (Ubx) and abdominal-A (abd-A) genes in Drosophila, via an epitope common to the carboxy terminal region of these two proteins. This antibody recognizes nuclear antigens present in the posterior thorax and abdomen of Schistocerca. We infer that it recognizes the Schistocerca homolog of UBX protein, and probably also of ABD-A. As the distribution of Schistocerca ABD-A protein is already known, we can use this reagent to map the expression of Schistocerca UBX in the thorax and anterior abdomen, where ABD-A is not expressed. Both the general domain, and many of the details, of UBX expression are remarkably conserved compared with Drosophila. Thus UBX expression extends back from T2 in the ectoderm (including the CNS), but only from A1 in the mesoderm. As noted for other bithorax complex genes in Schistocerca, expression begins in the abdomen, at or shortly before the time of segmentation. It only later spreads anteriorly to the thorax. For much of embryogenesis, the expression of UBX in the thoracic epidermis is largely restricted to the T3 limb. In this limb, UBX is strikingly regulated, in a complex pattern that reflects limb segmentation. Reviewing these and earlier observations, we conclude that evolutionary changes affect both the precise regulation of homeotic genes within segments, and probably also the spectrum of downstream genes that respond to homeotic gene expression in a given tissue. Overall domains of homeotic gene expression appear to be well conserved between different insect groups, though a change in the extent and timing of homeotic gene expression may underlie the modification of the posterior abdomen in different insect groups.

Amino Acid Sequence↗

PubMed1985

The distribution of Ultrabithorax transcripts in Drosophila embryos.

We have used in situ hybridization to monitor the distribution of Ultrabithorax (Ubx) transcripts during the early stages of Drosophila embryogenesis. When first detectable, in the late syncytial blastoderm, Ubx transcripts are broadly distributed from 20 to 50% egg length (measured from the posterior pole). By the completion of cellular blastoderm formation, a precisely bounded zone one segment wide is defined by the accumulation of high levels of Ubx transcripts. This zone is probably the primordium for parasegment 6, that is, the posterior compartment of the third thoracic segment (T3) and the anterior compartment of the first abdominal segment (A1). Following gastrulation, seven metameric units of the germ band express Ubx transcripts in most or all cells of both the ectoderm and the mesoderm. This principal domain of Ubx expression is sharply bounded at superficial grooves in the embryo which probably mark the A/P compartment boundaries in T3 and A7, and so consists of parasegments 6-12. Outside this region, Ubx transcripts can be detected in only a few cells of the ectoderm of parasegments 5 and 13, and in the amnioserosa. This distribution suggests that the major role of Ubx in the early embryo lies in the morphological domain generally ascribed to the control of the bithoraxoid gene. Later in embryogenesis, the pattern of Ubx transcript accumulation is different in each of the major germ layers, suggesting that different controls regulate Ubx in each. In the ectoderm, but not in the mesoderm, Ubx transcripts accumulate differentially in anterior and posterior compartments. Probes prepared from different regions of the Ubx transcription unit show related but different patterns of hybridization. These patterns suggest that the 3.2-kb Ubx transcript is distributed throughout the wider domain of Ubx expression, but that the 4.7-kb transcript accumulates preferentially in parasegment 6.

Journal Article↗

PubMed1985

Distribution of Ultrabithorax proteins in Drosophila.

We have used a monoclonal antibody to examine the distribution of Ultrabithorax (Ubx) proteins in Drosophila embryos and imaginal discs by immunofluorescence. Ubx proteins are nuclear and show a spatially restricted distribution in the nervous system, epidermis and mesoderm. Labelling extends from the first thoracic segment (T1) to the eighth abdominal segment (A8) in the midline cells, from T2 to A8 in the ventral nervous system and epidermis and from A1 to A8 in the somatic mesoderm. In the nervous systems and epidermis the patterns of labelling exhibit a repeat unit, the Ubx metamere, that is out of phase with the segmental repeat unit. At least in the epidermis this repeat unit appears to extend between anterior-posterior compartment boundaries and consists of a posterior compartment together with the succeeding anterior compartment. The most prominently labelled metamere in the nervous system and epidermis is that comprising the posterior region of T3 and the anterior region of A1. Within each metamere the nuclei are heterogeneously labelled. Clear heterogeneity of labelling is also seen amongst the nuclei of the T3 imaginal discs.

Journal Article↗

PubMed1985

Altered distributions of Ultrabithorax transcripts in extra sex combs mutant embryos of Drosophila.

The product of the extra sex combs (esc) gene is required early in embryogenesis to ensure the correct spatial expression of the bithorax and Antennapedia gene complexes during subsequent development. Here we describe the spatial and temporal patterns of transcription of the Ultrabithorax (Ubx) gene in mutant esc embryos. In wild-type embryos, Ubx transcripts are first detected in the blastoderm primorida of particular thoracic and abdominal segments, predominately in a band of cells constituting the progenitor cells of parasegment 6: after gastrulation, high levels of transcript accumulate in a sharply restricted region of the germ band comprising parasegments 6-12. In esc- embryos, the initial pattern of Ubx transcripts appears indistinguishable from that of wild-type embryos. However, following gastrulation and germ band extension, Ubx transcripts accumulate in most of the ectodermal and mesodermal derivatives of the body, including those of all 14 parasegments. Then, the abundance of the transcripts declines so that after germ band shortening (12 h after fertilization), only low levels are detected in each parasegment. These results show that the esc gene product is not involved in choosing where the Ubx gene is to be expressed, but rather, that it acts subsequently to ensure that the gene remains off in those primordia in which it is not initially activated. In addition, they suggest the possibility that other homeotic genes may regulate Ubx expression --in this case, the accumulating products of other indiscriminately expressed homeotic genes serving to down-regulate Ubx transcription throughout the body.

Animals↗

PubMed1987

Conserved sequence elements in the 5' region of the Ultrabithorax transcription unit.

Clones homologous to the 5' region of the Ultrabithorax gene of Drosophila melanogaster have been isolated from D. pseudoobscura, D. funebris and Musca domestica. Regions that encode most of the Ubx protein have been sequenced in all three of these species, and the 5' upstream region has been sequenced in D. funebris to a point 1000 bases upstream of the probable mRNA start site. Here we compare these sequences with those described elsewhere for D. melanogaster. Deduced amino acid sequences of the Ubx protein show 8% (D. pseudoobscura), 15% (D. funebris) and 22% (M. domestica) divergence from D. melanogaster. However, these figures mask very different rates of evolution in different regions of the protein. A glycine-rich (;hinge') region is conserved in each of these species, although its length is variable. Comparison of D. funebris and D. melanogaster sequences in the long 5' untranslated leader region of the mRNA, and in the region immediately upstream of the start point of transcription, reveals tightly conserved elements embedded in an otherwise non-homologous sequence. These conserved elements include a 118-bp region that spans the mRNA start site, an internally repetitive (TAA)(n) region in the untranslated leader and a short repeated motif immediately upstream of the ATG codon that initiates the major open reading frame of the Ubx protein. Two other conserved elements were identified upstream of the transcription start site; both elements have structural features consistent with a role as recognition sites for regulatory proteins.

Journal Article↗

PubMed1988

Alternative RNA products from the Ultrabithorax domain of the bithorax complex.

The homeotic gene, Ultrabithorax (Ubx) is involved in specifying the identities of several segments in the fly Drosophila melanogaster. The structures of over 60 independent Ubx cDNAs have been examined. There are two major species of transcripts, 3.2 and 4.3 kb in length, which are produced by alternate sites of polyadenylation. Differential splicing gives rise to at least five variant Ubx proteins. The variant forms share common 5' and 3' exons but differ in their small internal 'micro' exons. Additional variation is generated by two separate splice donor sites at the end of the common 5' exon, situated 27 bp apart. Northern hybridization and S1 nuclease protection studies of RNA from various developmental stages and tissue types reveal that the alternate splicing and the choice of polyadenylation site are each differentially regulated in both a temporal and a tissue specific manner. Additional transcripts were found just downstream of the Ubx transcription unit, which may be products of the lethal left of bithorax gene (llb).

Animals↗

PubMed1989

Coordinate action of a proximal homeoprotein binding site and a distal sequence confers the Ultrabithorax expression pattern in the visceral mesoderm.

Spatially regulated expression of the homeotic gene Ultrabithorax (Ubx) in the visceral mesoderm can be mimicked in transformed Drosophila embryos by expression of a Ubx--beta-galactosidase fusion gene. Here we show that a proximal homeoprotien binding sequence downstream of the Ubx transcription start site, the B element, is required for this pattern. A distal upstream Ubx sequence, but not the B element, is sufficient to confer the pattern if linked to an hsp70 TATA box in a heterologous construct. The pattern in this case requires Ubx function, like endogenous Ubx expression in the visceral mesoderm, suggesting that the distal upstream sequence contains an important target sequence for autoregulation. We propose that the B element, in the context of the Ubx promoter, functions to mediate enhancer function of the distal sequence. Thus, the visceral mesoderm pattern requires coordinate action of a proximal and a distal regulatory element.

Animals↗

PubMed1991

Long range repression conferring boundaries of Ultrabithorax expression in the Drosophila embryo.

In an attempt to reconstruct the embryonic expression pattern of the homeotic gene Ultrabithorax (Ubx) by stable integration of fusion constructs, we identified three key control regions called PBX, ABX and BXD. Each of these confers an expression pattern mimicking certain aspects of Ubx expression. The PBX and ABX patterns are limited to the Ubx domain with anterior boundaries at parasegments 6 and 5. In contrast, the BXD pattern extends from head to tail. PBX or ABX expression boundaries are imposed on the BXD pattern, if PBX or ABX is linked to BXD. These boundaries, although not the PBX and ABX expression limits themselves, are dependent on Polycomb function. We conclude that PBX and ABX are recognized by repressors which act across large distances to suppress BXD activity. Stable and heritable Ubx expression boundaries are thus mediated by this process of long range repression.

Animals↗

PubMed1991

Optimal DNA sequence recognition by the Ultrabithorax homeodomain of Drosophila.

The 61 amino acid homeodomain is conserved among members of a family of eukaryotic DNA-binding proteins that play regulatory roles in transcription and in development. We have refined a rapid method for determining optimal DNA binding sites and have applied it to a 72 amino acid peptide containing the homeodomain of the Ultrabithorax (Ubx) homeotic gene of Drosophila. The site (5'-TTAATGG-3') is tightly bound (KD approximately 7 x 10(-11) M) by the Ubx homeodomain peptide; the four central TAAT bases of this sequence play a primary role in determining the affinity of binding, with significant secondary contributions deriving from the flanking bases. Although previously defined genomic sites contain multiple TAAT sequences with flanking bases distinct from those in the optimal binding site, we have found a new binding site with seven near-perfect repeats of the optimal sequence; this site is located in the promoter region of decapentaplegic, a probable Ubx regulatory target. The presence of a TAAT motif in the binding sites for most other homeodomain proteins suggests the existence of a conserved mechanism for recognition of this core sequence, with further specificity conferred by interactions with bases flanking this core.

Animals↗

PubMed1992

Homeotic control in Drosophila; the scabrous gene is an in vivo target of Ultrabithorax proteins.

The regulatory functions of transcription factors encoded by the Ultrabithorax (Ubx) gene initiate genetic programmes essential for segmental identity and morphogenesis in Drosophila. Based on the formation of DNA-protein adducts in intact nuclei and immunoselection procedure, we cloned genomic targets for Ubx proteins. One clone was studied in detail. It encompasses parts of the last intron and exon of the scabrous (sca) gene, which encodes a secreted protein involved in cellular communication during neurogenesis. Five motifs, presenting the ATTA core, which is shared by most homeodomain binding sites, were found in the nucleotide sequence of this clone. We detail here the dynamic pattern of sca transcript accumulation during embryogenesis and show that mutation of Ubx results in the ectopic transcription of sca in the first abdominal segment. We propose that a direct interaction of Ubx with cis-acting elements in sca negatively regulates the gene. Transcript localization in several combinations of deficiencies in the Bithorax complex (BX-C) indicates that sca is downregulated by abdominal A (abdA) and Abdominal B (AbdB), and suggests that it is a common target of the three genes of BX-C.

Animals↗

PubMed1992

Trans regulation in the Ultrabithorax gene of Drosophila: alterations in the promoter enhance transvection.

We report a genetic and molecular study of UbxMX6 and Ubx195rx1, two mutations in the Ultrabithorax (Ubx) locus which appear to have a strong effect on the activity of the homologous Ubx gene. These mutations show the characteristic embryonic and adult phenotypes of Ubx null alleles, and also fail to produce any detectable Ubx product. Yet, genetic and phenotypic analyses involving a large number of trans heterozygous combinations of UbxMX6 and Ubx195rx1 with different classes of Ubx mutations, indicate that they hyperactivate the homologous gene. This effect is induced on wildtype or mutant forms of Ubx, provided that the pairing in the bithorax region is normal, i.e. these mutations have a strong positive effect on transvection. We also show that, unlike all the other known cases of transvection in Ubx, this is not zeste-dependent. Southern analyses indicate that UbxMX6 is a 3.4 kb deletion, and Ubx195rx1 is an approximately 11 kb insertion of foreign DNA, both in the promoter region. We speculate that the region altered in the mutations may have a wildtype function to ensure cis-autonomy of the regulation of Ubx transcription.

Alleles↗

PubMed1995

Ultrabithorax protein is necessary but not sufficient for full activation of decapentaplegic expression in the visceral mesoderm.

To elucidate the mechanisms by which homeotic selector (HOM) genes specify the unique features of Drosophila segments, we have analyzed the regulation of decapentaplegic (dpp), a transforming growth factor (TGF)-beta superfamily member, and have found that the Ultrabithorax (Ubx) HOM protein directly activates dpp expression in parasegment 7 (PS7) of the embryonic visceral mesoderm. Other factors are also required, including one that appears to act through homeodomain protein binding sites and may be encoded by extradenticle (exd). The exd protein binds in a highly co-operative manner to regulatory sequences mediating PS7-specific dpp expression, consistent with a genetic requirement for exd function in normal visceral mesoderm expression of dpp. A second mechanism contributing to PS7 expression of dpp appears not to require Ubx protein directly, and involves a general visceral mesoderm enhancer coupled to a spatially specific repression element. Thus, even in an apparently simple case where visceral mesoderm expression of the dpp target gene mirrors that of the Ubx HOM protein, full activation by Ubx protein requires at least one additional factor. In addition, a distinct regulatory mode not directly involving Ubx protein also appears to contribute to PS7-specific expression.

Animals↗

PubMed1997

A conserved cluster of homeodomain binding sites in the mouse Hoxa-4 intron functions in Drosophila embryos as an enhancer that is directly regulated by Ultrabithorax.

The evolutionary conservation of the homeodomains suggests that their in vivo DNA binding sites may also be conserved between vertebrates and invertebrates. The regulatory function of the mouse Hoxa-4 and Hoxb-4 introns were analyzed in Drosophila since they both contain a cluster of three homeodomain binding sites, the HB1 element, which was also found in the introns of other Hox genes ranging from fish to humans as well as in the Ultrabithorax (Ubx) and decapentaplegic (dpp) genes of Drosophila. The enhancer of the Hoxa-4 intron was found to respond to several homeobox genes activating a lacZ reporter gene in particular cells of the epidermis in Drosophila embryos. The enhancer activity was found to be similar to previously described autoregulatory elements of Deformed (Dfd), the Drosophila homolog of Hoxa-4, but additional expression was observed in more posterior segments activated by Ubx and repressed by abdominal-A (abd-A). Point mutations in the homeodomain binding sites in HB1 abolished the enhancer activity. A second site suppression experiment showed that UBX interacts directly with the HB1 element. When the HB1 element in the Hoxa-4 intron was replaced by that of the mesodermal enhancer of dpp, which was previously shown to be directly controlled by Ubx, Ubx-dependent activation was retained, but repression by abd-A was lost. The same result was obtained when the third binding site of HB1 was altered, suggesting that this site is responsible for abd-A-dependent repression. Finally, deletion of potential cofactor binding sites flanking the HB1 element that are also conserved in the medaka, chicken, and mouse genes revealed that they are important for enhancer function in Drosophila and that the Dfd-dependent and the Ubx-dependent expression requires different sites. The evolutionary and functional conservation of the HB1 elements indicates that not only the homeodomains but also some of their in vivo binding sites are conserved between vertebrates and invertebrates.

Animals↗

PubMed1999

Negative regulation of dorsoventral signaling by the homeotic gene Ultrabithorax during haltere development in Drosophila.

Growth and patterning during Drosophila wing development are mediated by signaling from its dorsoventral (D/V) organizer. In the metathorax, wing development is essentially suppressed by the homeotic selector gene Ultrabithorax (Ubx) to mediate development of a pair of tiny balancing organs, the halteres. Here we show that expression of Ubx in the haltere D/V boundary down-regulates its D/V organizer signaling compared to that of the wing D/V boundary. Somatic loss of Ubx from the haltere D/V boundary thus results in the formation of a wing-type D/V organizer in the haltere field. Long-distance signaling from this organizer was analyzed by assaying the ability of a Ubx(-) clone induced in the haltere D/V boundary to effect homeotic transformation of capitellum cells away from the boundary. The clonally restored wing D/V organizer in mosaic halteres not only enhanced the homeotic transformation of Ubx(-) cells in the capitellum but also caused homeotic transformation of even Ubx(+) cells in a genetic background known to induce excessive cell proliferation in the imaginal discs. In addition to demonstrating a non-cell-autonomous role for Ubx during haltere development, these results reveal distinct spatial roles of Ubx during maintenance of cell fate and patterning in the halteres.

Animals↗

PubMed1997

Modelling the activity of the Ultrabithorax parasegment-specific regulatory domains around their anterior boundaries.

The Drosophila Ultrabithorax (Ubx) gene was one of the first homeotic genes to be characterised and it specifies the phenotypic characteristics of parasegments 5 and 6. The intricate pattern of Ubx expression in these parasegments is conferred by enormous regulatory regions which, together with the structural gene, constitute the Ubx domain. A genetic, "open-for-business", model based on classical mutational analysis proposed that the regulatory regions were in fact composite structures, consisting of parasegment-specific regulatory domains that contain arrays of cell-specific enhancers which drive the intricate pattern of Ubx expression. Here, we propose a molecular mechanism, based on a survey of numerous transgenic studies, of the setting up of these parasegment-specific regulatory domains in the appropriate parts of the late blastoderm embryo. We construct a mathematical model of this mechanism using the molecular characteristics of a single initiator element, the distributions of segmentation gene products and simple competitive binding equations. We attempt to fit this mathematical model to the idealised patterns of activity and closure of the parasegment-specific domains derived from the genetic model. The resulting fitted pattern of activity and closure obtained with the simplest version of our competitive binding model shows some deviations from the idealised pattern based on the genetic model. Comparison of the predictions with recent experimental evidence suggests that the competitive binding model more accurately reflects certain features of the Ubx expression pattern--features not predicted by the genetic model.

Animals↗

PubMed1992

Positive and negative cis-regulatory elements in the bithoraxoid region of the Drosophila Ultrabithorax gene.

The Ultrabithorax (Ubx) gene is required during embryogenesis and larval development to specify the third thoracic and first abdominal segments of Drosophila melanogaster. Mutations in the bithoraxoid (bxd) region, a 40 kb DNA stretch upstream of the Ubx promoter, affect cis-regulatory elements responsible for the ectodermal expression of the Ubx gene in the posterior compartment of the third thoracic segment and anterior compartment of the first abdominal segment. Our genetic data and the available molecular information are used to map the adult epidermal cis-regulatory elements within the bxd region. Genetic combinations involving mutations affecting the bxd region show that (1) redundant or cooperatively acting sequences are required for Ubx gene expression in the anterior compartment of the first abdominal segment, and (2) the expression of Ubx in the posterior compartment of the third thoracic segment is modulated by positive and negative cis-regulatory elements.

Alleles↗

PubMed1996

A genetic analysis of bx bxd cis double mutants in the Drosophila Ultrabithorax gene.

The Ultrabithorax (Ubx) gene of Drosophila melanogaster includes two functionally distinguishable regions. One is the Ubx transcription unit, which gives rise by alternative splicing to a family of morphogenetic Ubx proteins (UBX). The other is its upstream bithoraxoid (bxd) region. On the basis of genetic and molecular studies, it is generally assumed that the Ubx transcription unit contains internal positively acting cis-regulatory elements controlling UBX expression in the T3a compartment of the body of Drosophila, while the bxd region contains positive cis-regulatory elements controlling UBX expression in the T3p and A1a compartments. We have performed a genetic analysis of bx bxd cis double mutant chromosomes containing one mutation (bx alleles) affecting the Ubx unit, and a second (bxd alleles) affecting the bxd region of the Ubx gene. Our study of different bx bxd/bx combinations shows that bxd alleles partially rescue the adult mutant phenotypes of bx alleles, which suggests that the bxd region contains a negative cis-regulatory element involved in the control of the activity of the Ubx gene in the T3a compartment.

Alleles↗