NFκB, GSd447, NF-κB
AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Some regions with low pLDDT may be unstructured in isolation.
Annotated transcripts do not represent all possible combinations of alternative exons and/or alternative promoters.
Low-frequency RNA-Seq exon junction(s) not annotated.
Gene model reviewed during 5.50
Click to get a list of regulatory features (enhancers, TFBS, etc.) and gene disruptions (point mutations, indels, etc.) within or overlapping Dmel\dl using the Feature Mapper tool.
The larger form of dl transcript is expressed in a tissue specific manner. It is present in larvae and adults of both sexes. The intensity of the band increases upon immune challenge especially in larvae and adult males. dl transcripts are present at low levels in the gut and fat body of unchallenged larvae. The levels are enhanced in the larval fat body after immune challenge. In embryos the larger dl transcript is present from 6-9hr embryos on through embryogenesis.
Only the larger isoform of dl protein can be found in larval neuromuscular junctions.
Expression of dl is seen in the neuromuscular junction of wildtype fly when observed at 3 and 60 days post-eclosion.
dl protein is diffusely distributed in the nucleus and cytoplasm of somatic muscles during the last hours of larval development, and though the first four hours of pupariation. dl protein is enriched in the subsynaptic reticulum of type I synaptic boutons. Four hours after pupariation, dl protein is shifted to the nucleus. In adults, the dl protein distibution is similar to that in larvae.
GBrowse - Visual display of RNA-Seq signalsView Dmel\dl in GBrowse 2
Please Note FlyBase no longer curates genomic clone accessions so this list may not be complete
Please Note This section lists cDNAs and ESTs that fall within the genomic extent of the gene model, which may include cDNAs and ESTs of genes within introns, or of overlapping genes. Please see GBrowse for alignment of the cDNAs and ESTs to the gene model.
For each fully sequenced cDNA the DGRC maintains various forms of the cDNA (e.g tagged or untagged) in several different host vectors for subsequent cloning and expression in Drosophila and Drosophila cell lines.
Gene expression is increased in response to the presence of two copies of Scer\GAL4hs.PB.
Targeting of either tub or pll product to the plasma membrane by myristylation is sufficient to activate the signal transduction pathway that leads to translocation of the dl product. Activated Tl induces a localized recruitment of tub and pll proteins to the plasma membrane.
Tl pathway is required for the nuclear import of dl in the immune response, but not required for the nuclear import of Dif. Cytoplasmic retention of both dl and Dif depends on cact protein. The two signalling pathways that target cact for degradation must discriminate between cact-dl and cact-Dif complexes.
Transcript induced by MMS treatment of S1CII cells.
The molecular evolution of the Rel/NF-κB and IκB proteins is studied in parallel. Phylogenetic analysis allows the structure of the putative ancestor genes to be defined and proposes and evolutionary model that clusters both families in a unique Rel/NF-κB/IκB superfamily.
dl and twi proteins synergistically activate transcription in cell culture from a promoter containing binding sites for both factors. The Rel homology domain of the dl protein appears to be sufficient for the synergy. Protein-protein interaction assays show that dl and twi proteins bind to one another in vitro.
cact forms a concentration gradient inversely correlated to the nuclear translocation gradient of dl. Genetic evidence indicates degradation of cact is required, but not sufficient, to translocate dl completely into the nucleus.
dl and Dif have distinct DNA-binding characteristics and the proteins can heterodimerise in vitro. Mutants carrying no copies of dl and a single copy of Dif retain their full capacity to express the Dpt and CecA1 genes in response to bacterial challenge.
The embryonic regulatory pathway, comprising the gene products between spz and cact (Tl, tub and pll) but not the genes acting upstream or downstream (ea and dl), is involved in the induction of the Drs gene in adults.
cact inhibits nuclear translocation of dl on the ventral side of the embryo by binding to and retaining dl in the cytoplasm. cact is rapidly degraded in response to signalling from the dorsal ventral pathway between spz and dl/cact, this signal-dependent degradation does not require the presence of dl but does require sequences in the amino terminus or ankyrin repeats of the cact protein. Disruption of the dl-cact complex is a secondary result of cact degradation.
Monitoring phosphorylation in mutant backgrounds demonstrates that phosphorylation of the dl protein is clearly affected. Therefore phosphorylation may play a role in regulating the dl protein. One of three mutations in the putative phosphorylation sites at residue 312, not at residue 290 or 324, markedly reduces the ability of the transgene to rescue dl mutant embryos.
Nuclear localisation of dl in the fat body during the immune response is controlled by the intracellular embryonic dorsoventral pathway, the Tl signalling pathway. dl alone does not control the expression of antibacterial peptide genes as these genes are inducible in its absence. dl is not involved in the formation of melanotic tumours of Tl or cact mutations nor in the induction of Dpt gene, or dl acts in concert with other proteins to affect cellular and/or humoral immunity.
The dl regulatory gradient defines the limits of inductive interactions between germ layers after gastrulation.
The tub protein can function in a novel way to enhance dl activity. In the absence of dl or when dl is cytoplasmic, tub is only found in the cytoplasm of transfected cells. When dl is localised to the nucleus, so is tub. tub can then function to enhance reporter gene expression, by cooperation with dl or as a Scer\GAL4-tub fusion protein. tub is capable of acting as both a chaperon or escort for dl as it moves to the nucleus and then as a transcriptional coactivator. The intracytoplasmic domain of Tl is sufficient for activating the signalling pathway that leads to dl-tub nuclear translocation in Schneider cells.
The dl-bHLH protein interactions mediating gene expression in the neuroectoderm and mesoderm are fundamentally distinct. Proximity between dl and bHLH binding sites is essential for synergistic activation of gene expression in the lateral neuroectoderm, where levels of dl product diminish. Sharp on/off patterns of gene expression in the presumptive mesoderm do not require linkage of these sites.
A sequence within the RHD (Rel homology domain) is essential for inhibitor interactions. Point mutations within this sequence can uncouple DNA binding and inhibitor interactions in vitro.
dl is an embryonic phosphoprotein and its phosphorylation state is regulated by an intracellular signaling pathway initiated by the transmembrane receptor Tl. Using a combined genetic and biochemical approach it is demonstrated that activation of Tl stimulates an increase in the extent of dl phosphorylation. Signal-dependent dl phosphorylation is modulated by three intracellular proteins, pll, tub and cact.
Dorsal-ventral patterning is regulated by a signalling pathway that includes Tl and transcription factors, dl, that interact with related enhancers, rho. The κ enhancer from mouse is capable of generating lateral stripes of Ecol\lacZ gene expression in transgenic embryos in a pattern similar to that directed by rho enhancer. Results suggest that enhancers can couple conserved signalling pathways to divergent gene functions, dorso-ventral patterning and mammalian haematopoiesis.
Disulfide cross-linking in crude extracts has identified two complexes of dl protein: a dl protein homodimer and a complex of the homodimer with cact protein. The distribution of the complex varies, the homodimer is the nuclear form of dl protein and a complex of the homodimer with cact protein prevails in the cytoplasm.
dl directly represses tld gene expression in ventral regions of the early embryo. DNaseI footprinting reveals dl binds to at least three sites in the tld 5' flanking sequences that are required in vivo for ventral repression (423bp VRE element).
Comparisons of early development to that in other insects have revealed conservation of some aspects of development, as well as differences that may explain variations in early patterning events.
The Tl signalling pathway generates a dl nuclear gradient which initiates the differentiation of the mesoderm, neuroectoderm and dorsal ectoderm by activating and repressing gene expression in the early embryo. A second signalling pathway controlled by the tor receptor kinase also modulates dl activity. The tor pathway selectively masks the ability of dl to repress gene expression but only has a slight effect on activation.
dl gene product interacts with members of the HLH family, including da, ac and sc and dosage sensitive interactions that exist between dl, da, ac, sc and twi are required for the specification of both the embryonic mesoderm and neuroectoderm.
Promoter fusions using elements of the twi, ve, da and sna promoters indicate that low affinity dl-binding sites restrict target gene expression to the presumptive mesoderm, where there are peak levels of dl expression, while high affinity sites in other target genes permit expression in ventrolateral regions where dl levels are intermediate. Activation by low levels of dl in lateral regions depends on cooperative interaction between dl and other basic helix loop helix proteins. Promoters containing the Et (veinlet) or Eds (dl and snail) E boxes display opposite behaviour in da and twi mutants, suggesting they are regulated by different basic helix loop helix proteins.
A minimal 110bp Ventral Repression Element silencer in the zen promoter contains two dl binding sites as well as binding sites for additional nuclear factors present in early embryos. Mutations in the latter convert the minimal VRE into an enhancer, mediating transcriptional activation in ventral regions in response to dl. Thus dl is converted from an activator to a silencer by interactions with neighboring corepressors.
dl binding sites from the zen promoter can mediate transcriptional activation of a heterologous promoter, but not repression. T-rich sequences close to the dl binding sites in the silencer region of the zen promoter are conserved between D.melanogaster, D.virilis and D.pseudoobscura.pseudoobscura.
Increased cytoplasmic calcium concentration and the expression of constitutively active Tl receptors can induce the relocalisation of dl in culture cells. Activation of endogenous Pka-C1, expression of wild type Tl receptors or treatment of cells with activators of Pkc53E and radical oxygen intermediates have only a marginal effects on the cellular distribution of dl protein.
Cytoplasmic injection studies indicate that the putative Toll ligand appears to originate from a ventrally restricted zone extending along the anterior-posterior axis, and its diffusion or graded release are required to determine the slope of the nuclear dorsal protein gradient.
dl and cact are phosphoproteins that form a stable cytoplasmic complex. The cact protein is stabilised by its interaction with dl protein, and the dl-cact complex dissociates when dl protein is targeted to the nucleus.
The zygotic dpp gradient and the maternal dorsal gradient specify distinct, non-overlapping domains of the dorsal-ventral pattern.
Double mutant combinations of dl with ea alleles demonstrate that spatial regulation of ea activity by localized zymogen activation is a key initial event in defining the polarity of the dorsal-ventral embryonic pattern.
In vitro studies showed the cactus gene product can inhibit binding of dorsal protein to DNA.
Expression of dl-lacZ fusion protein causes a partial loss of function dl phenotype, and downstream genes twi and zen are misregulated. The fusion protein localises to nuclei in manner indistinguishable from wild type dl protein. The dl-lacZ fusion provides some dl function: in a null dl background the fusion gene causes partial rescue of the phenotype. In vitro immunoprecipitation experiments show that dl and dl-lacZ proteins associate, suggesting that in wild type dl functions as an oligomer. Dominant female sterility caused by dl-lacZ is relieved by additional dl or Ecol\lacZ protein.
dl acts in concert with basic HLH proteins (possibly including twi) to activate ve in both ventral and lateral regions. A dl activator site has been found in the neural ectoderm expression region of the ve promoter.
Mutants of dl have been sequenced and their phenotypes studied. Results demonstrate that the dl protein has an amino terminal DNA binding domain and a carboxy terminal domain required for transcriptional activation/repression.
dl binding site domain exchange experiments, using Ecol\lacZ reporter gene constructs, between the zen and twi promoters demonstrate that dl is intrinsically an activator and that repression requires additional factors present in the distal region of the zen promoter, the VR.
Effects of Toll on dl in cotransfected Schneider cells examined: Toll can enhance nuclear localisation of dl and, independently, the ability of dl to activate transcription once in the nucleus. Pathway from Toll to dl may involve protein kinase A, and nuclear transport and activation of dl may result from phosphorylation of dl by protein kinase A.
The dl gene product is required for ventral repression of tll expression of the stripe: bcd function is also required.
The dl gene acts downstream of Tl: perivitelline fluid from dl mutant embryos is equivalent to that obtained from wild type embryos.
The effect of the terminal system on the expression of 2 zygotic genes involved in dorsoventral patterning, sna and dpp, is mediated by a reduction in dl activity by the terminal system. Due to this interaction the poles adopt a more dorsalised fate than their counterparts in the middle of the embryo.
dl is a sequence specific DNA binding protein that may mediate long range repression by interacting with the distal regions of the zen promoter. dl binding sites share sequence similarity with the conserved sites recognized by the rel and NF-ΚB proteins.
A combination of promoter fusion-P-element transformation assays (1.2kb twi promoter fragment is sufficient to generate normal twi pattern of Ecol\lacZ expression) and in vitro DNA binding assays coupled with site directed mutagenesis (revealing four dl-binding sites in the twi promoter) have been used to establish a link between the dl-binding sites and twi expression in early embryos. The dorsal ventral limits of twi expression depend on the number and affinity of dl binding sites present in the twi promoter. dl-binding sites present in the twi promoter possess a lower affinity to those present in the zen promoter.
Establishment of the mesoderm neuroectoderm boundary involves the interaction of twi, sna and dl proteins.
Footprint analysis has been used to analyse transcription activation factors responsible for ventral specific expression of twi. dl has been found to bind the ventral activation region of twi and interact directly or indirectly with other DNA bound regulatory factors to activate twi expression in the presumptive mesoderm.
Mutations in maternal dorsal class gene dl interact with RpII140wimp.
dl appears to activate the expression of twi and sna and repress the expression of zen and dpp. Polar expression of dpp and zen requires the terminal system to override the repression of dl, and twi and sna polar expression require the terminal system to augment activation of dl.
dl acts as a sequence specific trans-activator of the twi promoter. Gel retardation assays have been used to investigate binding of dl protein to synthetic oligonucleotides corresponding to the proximal and distal activator region of the twi promoter.
Involved in the regulatory hierarchy responsible for the asymmetric distribution and function of zygotic regulatory gene products along the DV axis of early embryos.
Establishment of the dl gradient involves selective nuclear transport. Truncated dl protein lacking C-terminal sequences accumulate predominantly in the nuclei of transfected Schneider cells while the full length protein is largely restricted to the cytoplasm.
Mutations in dl result in a maternal effect phenotype with defects during the early stages of gastrulation and defects in the dorsoventral axis; embryos derived from homozygous females are dorsalised.
Epistatic relationships exist between dorsalizing maternal effect mutations and "dppHin" alleles.
The expression of genes controlling neurogenesis is dependent on the previous activity of the genes controlling the development of the embryonic dorsal-ventral pattern.
In homozygous embryos invagination of the ventral presumptive mesodermal cells fails to occur and the resulting embryos are devoid of internal organs.
Embryos produced by homozygous dl females form normal cellular blastoderm but at gastrulation develop into yolk-filled tube of dorsal hypoderm. Hair pattern of cuticle characteristic of dorsal hypoderm; ventral structures, such as denticle belts, lacking. Normally, dorsal infoldings occupy entire circumference of embryo. Evidence of anterior-posterior differentiation includes possible mouth armature structures anteriorly, small spiracles posteriorly and orientation of hairs. The periodicity of stripes of ftz expression in pre-gastrulation embryos, as revealed by antibody staining, displays the pattern normally characteristic of the dorsum circumferentially in embryos produced by dl females (Carroll, Winslow, Twombly, and Scott, 1987). Embryos produced by dl/dl and dl/Df(2L)TW137 indistinguishable, suggesting dl to be amorphic. Penetrance complete; expression constant. Embryos of dl2 females lack all structures normally derived from the ventral half of the egg, including mesoderm, endodermal gut, ventral nervous system and ventral hypoderm. dl1 and to a lesser extent dl2, females produce embryos with reduced capacity for neurogenesis in response to an absence of dl function (Campos-Ortega, 1983). dl germ line-dependent; homozygous germ-line clones produce dorsalized embryos (Schupbach and Wieschaus, 1986). Embryos of dl/+ females produced at 29oC develop into comparatively normal-looking larvae; they mainly lack internal organs, such as mesoderm and parts of the anterior and posterior gut; often ventral hypoderm including denticle belts reduced; phenotype sensitive to genetic background. At 22oC, dl/+ females produce normal embryos. Developmental fate of ventrally located cells on cellular blastoderm apparently shifted to that of more dorsally located cells. The phenotype of embryos produced by dl/dl females partially rescued by the injection of wild-type cytoplasm but not RNA (Santamaria and Nusslein-Volhard, 1983; Anderson and Nusslein-Volhard, 1984). Developmental profiles show transcript to be present only in ovaries and pre-cellular-blastoderm stages of embryogenesis. In situ hybridization indicates that ovarian transcript accumulates in nurse cells from stage 5 to 11; number of transcripts per genome equivalent in these polytene cells remains low and constant until stage 10, at which time there is a dramatic increase in the relative numbers of transcripts. After a lag of one or two nuclear divisions, transcript begins to accumulate in the oocyte; by stage 12 there is little detectable transcript in the nurse cells. It appears as though the nurse-cell transcript is transferred to the oocyte and thus to the embryo; transcript seems to be uniformly distributed in stage 14 oocytes (Steward, Ambrosio, and Schedl, 1985). dl protein is uniformly distributed throughout cytoplasm of early embryo; in the syncytial blastoderm a gradient of expression is achieved by the graded transport of dl protein into nuclei, with the highest nuclear concentrations found ventrally; protein remains cytoplasmic dorsally. Maternal dorsalizing mutants prevent nuclear localization and ventralized embryos show dorsal as well as ventral nuclear localization (Steward, Zusman, Huang and Schedl, 1988; Rushlow, Han, Manley and Levine, 1989; Steward, 1989; Roth et al., 1989).