Disease relevance of Dfd

• In a search through 35 kb of Dfd sequences for additional transcriptional control elements, we have identified a 3.2 kb DNA fragment containing an enhancer that mimics the expression of Dfd in the subesophageal ganglion of the embryonic central nervous system [1].

High impact information on Dfd

• Dfd accomplishes this by directly activating the cell death promoting gene reaper (rpr) [2].
• We show that during early Drosophila development, the Hox protein Deformed (Dfd) maintains the boundary between the maxillary and mandibular head lobes by activating localized apoptosis [2].
• To test the role of the homeodomain in determining target specificity, we replaced the homeobox of Deformed with the homeobox of Ultrabithorax [3].
• With these strains we can induce the ectopic expression of Dfd protein in other segments at various stages of embryonic development [4].
• This possibility is supported by the finding that a Drosophila Dfd autoregulatory element supplies spatially localized expression in the hindbrain of mouse embryos [5].

Biological context of Dfd

• One of the ancestral homeobox genes that arose close to the root of the Eumetazoa appears to have given rise to Dfd, Scr, and the Antennapedia homeobox-class homeotic genes [6].
• With regard to imaginal development, lab and Dfd occupy adjacent non-overlapping expression domains in the peripodial cell layer of the eye-antennal disc, in patterns that are consistent with their adult mutant phenotypes and published fate maps [7].
• During embryogenesis, lab and Dfd exhibit limited overlapping expression in areas that are of no obvious significance to the development of larval head structures, but also in areas that may have consequences for imaginal development [7].
• 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 [8].
• Mutations in lab, like those in the Deformed and proboscipedia loci of the ANT-C, reveal a homoeotic phenotype only in the adult stage of the life cycle [9].

Anatomical context of Dfd

• Tc Deformed (Tc Dfd) is expressed in the blastoderm and the condensing germ rudiment in a region that gives rise to gnathal segments [10].
• When Tc Dfd is expressed throughout embryonic ectoderm under the control of P69B, the beetle protein autoregulates the endogenous Dfd gene [10].
• Lox6, a leech Dfd ortholog, is expressed in the central nervous system and in peripheral sensory structures [11].

Associations of Dfd with chemical compounds

• Although the position of the chimera relative to DNA, as judged by hydroxyl radical footprinting, is similar to that of the Dfd HD, the missing nucleoside and methylation interference patterns resemble those of the Ubx HD [12].

Physical interactions of Dfd

• First, we provide evidence that the Hox protein Deformed (Dfd) can interact with simple DNA-binding sites in Drosophila embryos in the absence of Exd, but this binding is not sufficient for transcriptional activation of reporter genes [13].
• The Drosophila protein DEAF-1 is a sequence-specific DNA binding protein that was isolated as a putative cofactor of the Hox protein Deformed (Dfd) [14].
• The Deformed binding site is essential for temporal and spatial expression of beta-galactosidase during embryogenesis but is not required in the adult [15].

Regulatory relationships of Dfd

• Mutant analyses demonstrate that Scr and Dfd regulate pb in their normal domains of expression during embryogenesis [16].
• The good correlation between the in vitro DNA binding preferences of these four Antp-type homeodomain proteins and their ability to specifically regulate a Dfd enhancer element in the embryo, suggests that the modest binding differences that distinguish them make an important contribution to their unique regulatory specificities [17].
• In the head, Deformed is required to activate Serrate transcription in the maxillary segment, where Serrate is required for normal mouth hook morphogenesis [18].
• The basic-leucine zipper protein Cap 'n' collar B (CncB) suppresses the segmental identity function of the Hox gene Deformed (Dfd) in the mandibular segment of Drosophila embryos [19].

Other interactions of Dfd

• The gnathal segments of Dfd and Scr mutant larvae are abnormal but not homeotically transformed [6].
• Given this unique ontogenetic and phylogenetic history and the observation that homeotic transformations produced by the lab, Dfd, and proboscipedia (pb) loci are manifested only in the adult, we suggest that distinct regulatory paradigms evolved for homeotic gene function in the development of the larval versus adult head [7].
• The wg product, in addition to that of Dfd, appears to be sufficient to activate the endogenous Dfd gene in many embryonic cells [20].
• Second, the orientation of the Deformed gene is inverted in D. pseudoobscura, providing it with a 5' to 3' direction of transcription identical to the remaining ANT-C homeobox genes with the exception of fushi tarazu [21].
• Prior developmental genetic analyses have shown that labial (lab) and Deformed (Dfd) are homeotic genes that function in the development of the embryonic (larval) and adult head [7].

Analytical, diagnostic and therapeutic context of Dfd

• Sequence analysis of a newly isolated Hirudo medicinalis cDNA containing an Antennapedia (Antp)-class homeobox suggests that the corresponding gene, Lox6, is an ortholog of the Drosophila Deformed (Dfd) gene [11].
• Site-specific mutagenesis of these four sites results in an element that has low affinity for Dfd protein when assayed in vitro and is nonfunctional when assayed in embryos [22].

References