PLoS Genetics最新文献

Copper is an essential micronutrient for all living organisms. Mutations in the copper-importing transporter CTR1/CHCA-1 are associated with a severe copper deficiency disorder in humans, for which no effective cures are currently available. Here, we develop C. elegans as a model for copper deficiency. We show that chca-1 mutant worms fed HT115 bacterial diet exhibited a severe developmental phenotype resulting from copper deficiency, reminiscent of the symptoms observed in human patients. Remarkably, this phenotype can be rescued by switching to OP50 bacterial diet or by supplementing HT115 bacterial diet with glutathione disulfide (GSSG), a metabolite enriched in OP50. Such dietary interventions remodeled the transcriptome of chca-1 mutants towards that of wild-type worms and upregulated the expression of CTR1/CHCA-1-like copper transporters, thereby ameliorating the mutant phenotype. Our findings establish C. elegans as a model for copper deficiency caused by CTR1/CHCA-1, suggesting that dietary interventions may offer a potential therapeutic approach for this severe disease.

Calcium release from intracellular stores influences synaptic response timing and magnitude. Despite the critical role of inositol trisphosphate (IP3)- and ryanodine receptor (RyR)-dependent calcium release in regulating synaptic strength, the upstream signaling mechanisms that govern IP3 receptor or RyR activity remain elusive. Here, we provide evidence that the ArfGAP-containing protein Asap modulates NMJ morphogenesis and synaptic calcium homeostasis by activating IP3-mediated calcium release from the endoplasmic reticulum (ER) via the phospholipase C-beta (PLCβ) signaling pathway. Using CRISPR/Cas9-engineered Asap mutants and genetically encoded calcium sensors, we demonstrate that loss of Asap leads to elevated resting synaptic calcium, resulting in increased evoked amplitude, elevated spontaneous miniature frequency, and reduced synaptic failures under low extracellular calcium conditions. Additional pharmacological and genetic manipulations of calcium regulatory pathways further support the role of increased resting intracellular calcium in driving enhanced neurotransmission in Asap-deficient synapses. Consistent with the role of Asap's ArfGAP domain in NMJ morphogenesis and intracellular calcium regulation, expressing a GDP-locked form of Arf6 (Arf6DN) or knocking down Arf6 in Asap mutants not only rescues Asap-associated synaptic defects but also normalizes synaptic calcium levels. Furthermore, epistatic analysis revealed that attenuation of IP3-signaling components in animals constitutively expressing Arf6CA normalized the NMJ morphological defects and synaptic functions. Together, these findings provide novel insights into the role of Asap-Arf6-PLCβ signaling in IP3-regulated calcium dynamics, sustaining both structural and functional synaptic plasticity.

Mowat-Wilson Syndrome (MWS) is an autosomal dominant genetic disorder caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 (ZEB2) gene. Congenital anomalies of the kidney and urinary tract (CAKUT), including hydroureter and hydronephrosis, have been reported in patients with MWS. However, the role of the ZEB2 gene in urinary tract development and the cellular and molecular mechanisms underlying the CAKUT phenotypes in MWS remain unknown. In this study, we examined ZEB2 expression in the developing mouse ureter and generated Zeb2 ureteral mesenchyme-specific conditional knockout mice (Zeb2 cKO) by crossing Zeb2 floxed mice with Tbx18Cre mice. The urinary tract of Zeb2 cKO mice and their wild-type littermates was analyzed for morphological and histological changes. Our results show that ZEB2 is expressed in TBX18+ ureteral mesenchymal cells during mouse ureter development. Deleting Zeb2 in these cells caused hydroureter and hydronephrosis, indicating obstructive uropathy. Cellular and molecular marker analysis revealed that the TAGLN+ACTA2+ ureteral smooth muscle cell (SMC) layer was absent in Zeb2 cKO mice. In contrast, the tunica adventitia cell layer was significantly expanded compared to controls. At the molecular level, Zeb2 cKO mice had significantly decreased TBX18 expression but increased SOX9 expression in the developing ureter compared to wild-type controls. Our findings demonstrate that ZEB2 is crucial for normal ureteral SMC differentiation during ureter development. Additionally, our study suggests that MWS patients may have abnormal ureteral SMC development, which contributes to the abnormalities of the urinary tract.

Organisms evolve behavioral and morphological traits to adapt to their ecological niches, yet the genetic basis of adaptation remains largely unknown. Drosophila suzukii has evolved a distinctive oviposition preference for ripe fruit, unlike most Drosophila species such as D. melanogaster, which prefer overripe fruit. Carbon dioxide (CO2), a metabolic volatile that increases as fruit ripens and decays, may act as a critical ecological cue shaping these preferences. Here, we focus on D. suzukii and its sister species D. subpulchrella, which shows an intermediate preference, to investigate the genetic basis of CO2 responses. We report a previously unrecognized shift in CO2-guided oviposition: D. suzukii and D. subpulchrella readily lay eggs on CO2-enriched substrates, unlike the strong aversion displayed by D. melanogaster. Electrophysiological recordings revealed a species-specific sensory tuning, characterized by an early spike in CO2-evoked neuronal firing in D. suzukii and D. subpulchrella-a temporal response feature absent in D. melanogaster. To dissect the genetic basis of this shift, we generated transgenic D. melanogaster expressing either the D. suzukii Gr63a coding sequence or the D. subpulchrella Gr63a cis-regulatory element. Remarkably, both manipulations reproduced the early-onset firing pattern of CO2 sensitivity, demonstrating that either receptor function or expression can independently drive this sensitivity adaptation. Our findings reveal that evolution can shape ecological adaptation through distinct genetic mechanisms, leading to convergent physiological traits among closely related species.

Matrix metalloproteinases (MMPs) play crucial roles in both physiological and pathological conditions by degrading the extracellular matrix; however, the roles and regulatory mechanisms of MMPs in brain development remain insufficiently understood. In this study, using the lepidopteran insect Helicoverpa armigera, the cotton bollworm, a serious agricultural pest, as an experimental model, we revealed that MMP2 is an important factor in insect brain development during metamorphosis under steroid hormone 20-hydroxyecdysone (20E) regulation. MMP2 is highly expressed in the brain during metamorphosis. MMP2 is localized in some surface and internal cells in the brain during metamorphosis. The knockdown of Mmp2 by RNA interference in larvae repressed brain development, accompanied by an increase in autophagy and a decrease in cell proliferation. In addition, the nutrient levels of glucose and glutamate decreased in the brain, and the expression of glucose transporters and glutamate transporters decreased after Mmp2 was knocked down. The transcription of Mmp2 was upregulated by 20E via the transcription factor forkhead box O (FOXO) in a time- and concentration-dependent manner. These data suggest that MMP2 facilitates neural cell proliferation and nutrient supply, and ultimately regulates brain development during insect metamorphosis.

The complexity of varied modifications of chromatin composition is integrated in archetypal combinations called chromatin states that predict the local potential for transcription. The degree of conservation of chromatin states has not been established amongst plants, and how they interact with transcription factors is unknown. Here we identify and characterize chromatin states in the flowering plant Arabidopsis thaliana and the bryophyte Marchantia polymorpha, showing a large degree of functional conservation over more than 450 million years of land plant evolution. We used this new resource of conserved plant chromatin states to understand the influence of chromatin states on gene regulation. We established the preferential association of chromatin states with binding sites and activity of transcription factors. These associations define three main groups of transcription factors that bind upstream of the transcription start site, at the + 1 nucleosome or further downstream of the transcription start site and broadly associate with distinct biological functions including a list of potential candidate pioneer factors we know little about in plants, compared to their important roles in animal stem cells and early development.

[This corrects the article DOI: 10.1371/journal.pgen.1007263.].

[This corrects the article DOI: 10.1371/journal.pgen.1011655.].

Transposable elements (TEs) are key agents of genome evolution across all domains of life. These mobile genetic elements can cause mutations through transposition or by promoting structural rearrangements. Stress conditions can amplify TE mobility, either by impairing TE suppression mechanisms or through stress-induced interactions between transcription factors and TE sequences, offering a route for rapid genetic change. As such, TEs represent an important source of adaptability within populations. To investigate the interplay between environmental stress and eukaryotic TE dynamics relevant to infectious disease, we examined how heat stress and host-mimicking medium (RPMI) affect TE mobility in the global human fungal pathogen Cryptococcus neoformans, using a collection of clinical and environmental isolates. Using a selection-based screen, we captured the mobilization of seven distinct mobile element families, encompassing diverse retrotransposons and DNA transposons, whose insertions conferred antifungal resistance. This includes a novel element, CNEST, which belongs to the CACTA, Mirage, Chapaev (CMC) supergroup. Heat stress at human body temperature (37°C) significantly increased the mobilization of a subset of these TEs, leading to higher rates of acquired antifungal resistance. Whole-genome assemblies revealed that, compared to retrotransposons, DNA transposons were hypomethylated and approximately uniformly distributed throughout the genome, features that may contribute to their frequent mobilization. We further assessed TE-driven genomic changes within hosts using serial isolates from patients with recurrent cryptococcal infections and from isolates passaged through mice. While we observed evidence of TE copy number changes near chromosome ends, we found no indication of TE-mediated alterations near gene-coding regions across any of the serial isolates. Finally, TE mobility was isolate- and strain-dependent, with significant variation even among clonally related strains collected from the same patient, emphasizing the role of genetic background in shaping TE activity. Together, these findings reveal a complex and dynamic relationship between environmental stress, genetic background, TE type-specific epigenetic regulation, and TE mobility, with important implications for adaptation and acquired antifungal resistance in C. neoformans.