The Homeodomain Protein Defective Proventriculus Is Essential for Male Accessory Gland Development to Enhance Fecundity in Drosophila

The Drosophila male accessory gland has functions similar to those of the mammalian prostate gland and the seminal vesicle, and secretes accessory gland proteins into the seminal fluid. Each of the two lobes of the accessory gland is composed of two types of binucleate cell: about 1,000 main cells and 40 secondary cells. A well-known accessory gland protein, sex peptide, is secreted from the main cells and induces female postmating response to increase progeny production, whereas little is known about physiological significance of the secondary cells. The homeodomain transcriptional repressor Defective proventriculus (Dve) is strongly expressed in adult secondary cells, and its mutation resulted in loss of secondary cells, mononucleation of main cells, and reduced size of the accessory gland. dve mutant males had low fecundity despite the presence of sex peptide, and failed to induce the female postmating responses of increased egg laying and reduced sexual receptivity. RNAi-mediated dve knockdown males also had low fecundity with normally binucleate main cells. We provide the first evidence that secondary cells are crucial for male fecundity, and also that Dve activity is required for survival of the secondary cells. These findings provide new insights into a mechanism of fertility/fecundity

A prospective compound screening contest identified broader inhibitors for Sirtuin 1

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Behaviors of females mated with <i>dve</i> mutant males.

<p>Postmating response of a wild-type female mated with a male of the indicated genotype. (A) The average number of progeny during 4 days. WT: wild-type male. A female mated with a <i>dve-A</i> mutant male (<i>dve^E181</i> or <i>dve^E181/dve^E144</i>) has reduced number of progeny compared with heterozygous controls. (B) The average number of eggs laid in a day. (C and D) Remating rate with a wild-type male at 4 hr (C) and 48 hr (D) after first mating with the indicated male. Mating rate of WT virgin females is also shown (black bar). Egg laying (B) and remating rate at 48 hr (D) of females mated with <i>dve</i> mutant males are comparable to those of virgin female controls. Error bars show SEM (** p<0.001, one-way ANOVA).</p

Schematic diagram of Dve functions during accessory gland development.

<p>Dve is strongly expressed in adult secondary cells (magenta) and undetectable in adult main cells (green). The main cells secrete sex peptide that is essential for long-term postmating response to increase progeny production. The Dve activity is required for proper development of these cells: survival of the secondary cells and binucleation of the main cells. An unknown factor X secreted from the secondary cells is essential for increasing progeny production, i.e., high fecundity.</p

Secondary cell precursors are detectable in <i>dve</i> mutants.

<p>(A and B) Accessory glands of a control male (A: <i>dve^E181/CyOGFP</i>) and a <i>dve-A</i> mutant male (B: <i>dve^E181/dve^E144</i>) at 72 hr APF. Nuclei are labeled in magenta with anti-Prd antibody. The control secondary cell precursors (outlined in A′) strongly express Abd-B (green). A <i>dve-A</i> mutant accessory gland has a few secondary cell precursors in which Prd expression is greatly reduced (outlined in B′). (C and D) Accessory glands of 4-days old adults are labeled with anti-Prd (red) and anti-Abd-B (green) antibodies. (C) Loss of secondary cells in <i>dve-A</i> mutants is rescued by expressing <i>dve-A</i> (<i>w; dve^E181/dve^E144; dG30A/UAS-dveA-9B2</i>). (D) Loss of secondary cells in <i>dve-A</i> mutants is also rescued by expressing <i>dve-B</i> (<i>w; dve^E181/dve^E144; dG30A/UAS-dveB-Y4N</i>). The rescued secondary cells are outlined. They express Abd-B (white in C′ and D′) and have vacuole components that are non-specifically stained with anti-Prd antibody (red in C′ and D′).</p

Localization of sperm and SP derived from <i>dve</i> mutant males.

<p>(A) Female reproductive organs, uterus (ut), seminal receptacle (src), and spermatheca (spt), are visualized with DNA staining (magenta) at 30 min after mating. The Protamine B-GFP fusion proteins (ProB::GFP, green) are localized in the sperm nuclei. (B–G) Localization of control sperms (B–D) and <i>dve-A</i> mutant sperms (E–G) in reproductive organs of wild-type females at 30 min after mating. The <i>dve-A</i> mutant sperms are correctly localized to the sperm storage organs (src and spt). (H–J) Localization of the sex peptide-GFP fusion proteins (SP::GFP, green) in reproductive organs of wild-type females at 20–30 min after mating. Females mated with control (H), <i>dve-A</i> mutant (I), and <i>dve</i> KD (J) males are shown. Arrows indicate the sperm mass and arrowheads indicate the posterior mating plugs.</p