The Hox gene Abdominal-B antagonizes appendage development in the genital disc of Drosophila

In Drosophila, the Hox gene Abdominal-B is required to specify the posterior abdomen and the genitalia. Homologues of Abdominal-B in other species are also needed to determine the posterior part of the body. We have studied the function of Abdominal-B in the formation of Drosophila genitalia, and show here that absence of Abdominal-B in the genital disc of Drosophila transforms male and female genitalia into leg or, less frequently, into antenna. These transformations are accompanied by the ectopic expression of genes such as Distal-less or dachshund, which are normally required in these appendages. The extent of wild-type and ectopic Distal-less expression depends on the antagonistic activities of the Abdominal-B gene, as a repressor, and of the decapentaplegic and wingless genes as activators. Absence of Abdominal-B also changes the expression of Homothorax, a Hox gene co-factor. Our results suggest that Abdominal-B forms genitalia by modifying an underlying positional information and repressing appendage development. We propose that the genital primordia should be subdivided into two regions, one of them competent to be transformed into an appendage in the absence of Abdominal-B.     

Regulation of body pigmentation by the Abdominal-B Hox protein and its gain and loss in Drosophila evolution

Hox genes have been implicated in the evolution of many animal body patterns, but the molecular events underlying trait modification have not been elucidated. Pigmentation of the posterior male abdomen is a recently acquired trait in the Drosophila melanogaster lineage. Here, we show that the Abdominal-B (ABD-B) Hox protein directly activates expression of the yellow pigmentation gene in posterior segments. ABD-B regulation of pigmentation evolved through the gain of ABD-B binding sites in a specific cis-regulatory element of the yellow gene of a common ancestor of sexually dimorphic species. Within the melanogaster species group, male-specific pigmentation has subsequently been lost by at least three different mechanisms, including the mutational inactivation of a key ABD-B binding site in one lineage. These results demonstrate how Hox regulation of traits and target genes is gained and lost at the species level and have general implications for the evolution of body form at higher taxonomic levels.     

The Number of Larval Molts Is Controlled by Hox in Caterpillars

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ARMC4 Mutations Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry

The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which are preassembled in the cytoplasm prior to transport to the ciliary axonemal compartment. In humans, defects in structural components, docking complexes, or cytoplasmic assembly factors can cause primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease and defects in laterality. By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating. Transient suppression in zebrafish and analysis of an ENU mouse mutant confirmed in both model organisms that ARMC4 is critical for left-right patterning. We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs.     

Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill

Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68×10⁻⁹), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR≤5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR≤5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.     

The Tolkin Gene Is a Tolloid/Bmp-1 Homologue That Is Essential for Drosophila Development

The Drosophila decapentaplegic (dpp) gene, a member of the tranforming growth factor β superfamily of growth factors, is critical for specification of the embryonic dorsal-ventral axis, for proper formation of the midgut, and for formation of Drosophila adult structures. The Drosophila tolloid gene has been shown to genetically interact with dpp. The genetic interaction between tolloid and dpp suggests a model in which the tolloid protein participates in a complex containing the DPP ligand, its protease serving to activate DPP, either directly or indirectly. We report here the identification and cloning of another Drosophila member of the tolloid/bone morphogenic protein (BMP) 1 family, tolkin, which is located 700 bp 5' to tolloid. Its overall structure is like tolloid, with an N-terminal metalloprotease domain, five complement subcomponents C1r/C1s, Uegf, and Bmp1 (CUB) repeats and two epidermal growth factor (EGF) repeats. Its expression pattern overlaps that of tolloid and dpp in early embryos and diverges in later stages. In larval tissues, both tolloid and tolkin are expressed uniformly in the imaginal disks. In the brain, both tolloid and tolkin are expressed in the outer proliferation center, whereas tolkin has another stripe of expression near the outer proliferation center. Analysis of lethal mutations in tolkin indicate it is vital during larval and pupal stages. Analysis of its mutant phenotypes and expression patterns suggests that its functions may be mostly independent of tolloid and dpp.     

The Centriolar Protein Bld10/Cep135 Is Required to Establish Centrosome Asymmetry in Drosophila Neuroblasts

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Fast sequence evolution of Hox and Hox -derived genes in the genus Drosophila

Background  

It is expected that genes that are expressed early in development and have a complex expression pattern are under strong purifying selection and thus evolve slowly. Hox genes fulfill these criteria and thus, should have a low evolutionary rate. However, some observations point to a completely different scenario. Hox genes are usually highly conserved inside the homeobox, but very variable outside it.     

Abdominal-B is essential for proper sexually dimorphic development of the Drosophila gonad

Sexual dimorphism requires the integration of positional information in the embryo with the sex determination pathway. Homeotic genes are a major source of positional information responsible for patterning along the anterior-posterior axis in embryonic development, and are likely to play a critical role in sexual dimorphism. Here, we investigate the role of homeotic genes in the sexually dimorphic development of the gonad in Drosophila. We have found that Abdominal-B (ABD-B) is expressed in a sexually dimorphic manner in the embryonic gonad. Furthermore, Abd-B is necessary and sufficient for specification of a sexually dimorphic cell type, the male-specific somatic gonadal precursors (msSGPs). In Abd-B mutants, the msSGPs are not specified and male gonads now resemble female gonads with respect to these cells. Ectopic expression of Abd-B is sufficient to induce formation of extra msSGPs in additional segments of the embryo. Abd-B works together with abdominal-A to pattern the non-sexually dimorphic somatic gonad in both sexes, while Abd-B alone specifies the msSGPs. Our results indicate that Abd-B acts at multiple levels to regulate gonad development and that Abd-B class homeotic genes are conserved factors in establishing gonad sexual dimorphism in diverse species.     

Is Function of the Drosophila Homeotic Gene Ultrabithorax Canalized?

Genetic variation affecting the expressivity of an amorphic allele of the homeotic gene Ultrabithorax, (Ubx(1)) was characterized after 11 generations of introgression into 29 different isofemale lines. Heterozygotes display a range of haploinsufficient phenotypes, from overlap with wild-type halteres to dramatic transformations such as a 50% increase in area and the presence of over 20 bristles on the anterior margin of each haltere. In both the wild-type and mutant genetic backgrounds, there is moderate genetic variance and low environmental variance/developmental asymmetry, as expected of a trait under stabilizing selection pressure. Surprisingly, there is little evidence that mutant halteres are more variable than wild-type ones, so it is unclear that haltere development is also canalized. The correlation between wild-type and Ubx haltere size is very low, indicating that interactions among modifiers of Ubx are complex, and in some cases sex-specific. The potential quantitative genetic contributions of homeotic genes to appendage morphology are discussed, noting that population-level effects of variation in key regulatory genes may be prevalent and complex but cannot be readily extrapolated to macroevolutionary diversification.     

Cholinergic Neuron-Specific Expression of the Human Choline Acetyltransferase Gene Is Controlled by Silencer Elements

Abstract: Choline acetyltransferase (ChAT) is specifically expressed in Cholinergic neurons. To identify control mechanisms regulating the cell-specific expression of the gene encoding ChAT, transient expression of the luciferase gene driven by human ChAT gene 5' flanking sequences was compared in cholinergic and noncholinergic cell lines. Analysis of the gene indicated the presence of two regulatory elements with selective silencing activity. These elements, located between nucleotides −2043 to −3347 and nucleotides −3347 to −6550, act cooperatively to repress promoter activity > 10-fold in a human adrenergic neuroblastoma cell line, SHSY5Y, and a human osteosarcoma cell line, 143 TK, while exhibiting less than a two-fold effect in Cholinergic cell lines. Deletion of either nucleotides −2043 to −3347 or nucleotides −3348 to −6550 reduced cell-specific repression by approximately half. Such differential repression appears to be responsible for the selective expression of the ChAT component of the Cholinergic phenotype.