PLoS Genet. [JOURNAL]
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200 papers
PERADIGM: Phenotype embedding similarity-based rare disease gene mapping.
Zheng W, Xie Y, Gu J … +4 more , Li H, Somlo S, Besse W, Zhao H
PLoS Genet · 2025 Dec · PMID 41411243 · Full text
Identifying genes associated with rare diseases remains challenging due to the scarcity of patients and the limited statistical power of traditional association methods. Here, we introduce PERADIGM ( Phenotype Embedding...
Identifying genes associated with rare diseases remains challenging due to the scarcity of patients and the limited statistical power of traditional association methods. Here, we introduce PERADIGM ( Phenotype Embedding similarity-based RAre DIsease Gene Mapping), a novel framework that leverages natural language processing techniques to integrate comprehensive phenotype information from electronic health records for rare disease gene discovery. PERADIGM employs an embedding model to capture relationships between ICD-10 codes, providing a nuanced representation of individual phenotypes. By utilizing patient similarity scores, it enhances the identification of candidate genes associated with disease-specific phenotypes, surpassing conventional methods that rely on binary disease status. We applied PERADIGM to the UK Biobank dataset for three rare diseases: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1). PERADIGM identified additional candidate genes associated with ADPKD-related and Marfan syndrome-related phenotypes, some of which are supported by existing literature, and demonstrated enhanced signal detection for NF1-specific phenotypes beyond traditional methods. Our findings demonstrate the potential of PERADIGM to identify genes associated with rare diseases and related phenotypes by incorporating phenotype embeddings and patient similarity, providing a powerful tool for precision medicine and a deeper understanding of rare disease genetics and clinical manifestations.
Reprogramming the EnvZ-OmpR two-component system confers ethanol tolerance in Escherichia coli by stabilizing the outer membrane and altering ferric homeostasis.
Schalck T, Katyal M, De Graeve S … +5 more , Roba L, Baldoma JV, Swings T, Van den Bergh B, Michiels J
PLoS Genet · 2025 Dec · PMID 41406166 · Full text
Ethanol is a fermentation product widely used as a fuel and chemical precursor in various applications. However, its accumulation imposes severe stress on the microbial producer, leading to significant production losses....
Ethanol is a fermentation product widely used as a fuel and chemical precursor in various applications. However, its accumulation imposes severe stress on the microbial producer, leading to significant production losses. To address this, improving a strain's ethanol tolerance is considered an effective strategy to enhance production. In our previous research, we conducted an adaptive evolution experiment with Escherichia coli growing under gradually increasing concentrations of ethanol, which gave rise to multiple hypertolerant populations. Based on the genomic mutational data, we demonstrated in this work that adaptive alleles in the EnvZ-OmpR two-component system drive the development of ethanol tolerance in E. coli. Specifically, when a single leucine was substituted for a proline residue within the periplasmic domain using CRISPR, the mutated EnvZ osmosensor caused a significant increase in ethanol tolerance. Through promoter fusion assays, we showed that this particular mutation stabilizes EnvZ in a kinase-dominating state, which reprograms signal transduction involving its cognate OmpR response regulator. Whole-genome proteomics analysis revealed that this altered signaling pathway predominantly maintains outer membrane stability by upregulating global porin levels and attenuating ferric uptake and metabolism in the tolerant envZ*L116P mutant. Moreover, we demonstrated that the hypertolerant envZ*L116P allele also promotes ethanol productivity in fermentation, providing valuable insights for enhancing industrial ethanol production.
Establishment and maintenance of NRT2.1 inter-individual variability in plants.
Lecuyer C, Vettor A, Fizames C … +5 more , Javot H, Martin A, Mazouzi M, Montané MH, Cortijo S
PLoS Genet · 2025 Dec · PMID 41406160 · Full text
Morphological phenotype and gene expression differences are observed between genetically identical plants grown in the same environment. While we now have a good understanding of the source and consequences of transcript...
Morphological phenotype and gene expression differences are observed between genetically identical plants grown in the same environment. While we now have a good understanding of the source and consequences of transcriptional differences observed between cells, our knowledge is still very limited regarding variability between multicellular organisms. We characterised this variability using the high-affinity nitrate transporter gene NRT2.1 as a model for high inter-individual transcriptional variability. Thanks to a combination of live imaging and transcriptomics, we show that the differences in expression of this gene between plants are established in young seedlings and maintained for up to three weeks. However, the expression level of NRT2.1 in plants does not permit predicting its expression in the next generation. Our results also indicate that these expression differences could have phenotypic consequences on root growth and nitrate uptake mediated by NRT2.1. Finally, we observed enriched photosynthesis-related functions among genes whose expression correlates with NRT2.1 in individual seedlings. Our study thus demonstrates that a global coordination of the genes involved in the carbon/nitrogen (C/N) balance in plants is established in young seedlings, at different levels in each plant, and maintained over time. Our results also highlight the fact that not all transcriptional regulators of NRT2.1 were identified, and propose UNE10 as a transcription factor for further study focused on its possible involvement in this pathway. This work shows that thanks to single-plant analysis of gene expression, we can gain new knowledge on the mechanisms behind a phenotype of interest that is normally masked in studies performed on pooled plants.
Genome-wide identification of genes involved in beetle odoriferous defensive stink gland function recognizes Laccase2 as the phenoloxidase responsible for toxic para-benzoquinone synthesis.
Atika B, Lehmann S, Buchberger E … +5 more , Dan'azumi Isah M, Basirkazerouni Z, Rostás M, Bucher G, Wimmer EA
PLoS Genet · 2025 Dec · PMID 41397024 · Full text
Exocrine glands have evolved several times independently in Coleoptera to produce defensive chemical compounds with repellent, antimicrobial, or toxic effects. Research on such glands had focused on morphological or chem...
Exocrine glands have evolved several times independently in Coleoptera to produce defensive chemical compounds with repellent, antimicrobial, or toxic effects. Research on such glands had focused on morphological or chemical ecology methods. However, modern genetic approaches were missing to better understand this biological process. With the rise of the red flour beetle, Tribolium castaneum, as a model for studies of development and pest biology, molecular genetic tools are now available to also study the safe generation of toxic compounds in defensive stink glands. Using the RNA-interference-based, genome-wide, phenotypic screen "iBeetle" and the re-analysis of gland-specific transcriptomics based on a significantly improved genome annotation, we could identify 490 genes being involved in odoriferous stink gland function. In the iBeetle screen, 247 genes were identified, of which we present here 178 genes identified during iBeetle's 3rd phase, while the transcriptomics analyses identified 249 genes, with six genes being identified in both functional genomics approaches. Of these 490 genes, only about 40% of these genes have molecularly characterized homologs in the vinegar fly, while for 213 genes no fly homologs were recognized and for 13 genes no gene ontology at all was identified. This highlights the importance of genome-wide gene identification in tissues that have not been previously analyzed to recognize potentially new gene functions. Gene ontology analysis revealed "SNARE interactions in vesicular transport", "Lysosome", "Pancreatic secretion", and "MAPK signaling pathway - fly" as key pathways. Additionally, many of the genes are encoding enzymes, transcription factors, transporters, or are involved in membrane trafficking. As the phenoloxidase responsible for generating the toxic para-benzoquinones in the stink glands of the beetle, we could identify laccase2, which is expressed in the last secretory cell in contact with the cuticle-lined vesicular organelle, where the toxic compounds are safely produced before being released into the gland reservoir.
Correction: The MIR157-SPL15 module regulates flowering and inflorescence development in Arabidopsis thaliana under short days and in Arabis alpina.
PLOS One Staff
PLoS Genet · 2025 Dec · PMID 41396868 · Full text
[This corrects the article DOI: 10.1371/journal.pgen.1011799.].
[This corrects the article DOI: 10.1371/journal.pgen.1011799.].
6-4 photolyase differentially modulates transcription in the vertebrate circadian clock.
Li H, Scheitle C, Hu X … +5 more , Kaiber JJ, Todo T, Vallone D, Fischer R, Foulkes NS
PLoS Genet · 2025 Dec · PMID 41385600 · Full text
The cryptochrome-photolyase family, a highly conserved set of flavoproteins, mediates many direct and indirect responses to sunlight. While the photolyases are light-dependent enzymes which catalyze photoreactivation rep...
The cryptochrome-photolyase family, a highly conserved set of flavoproteins, mediates many direct and indirect responses to sunlight. While the photolyases are light-dependent enzymes which catalyze photoreactivation repair of UV-induced DNA damage, the cryptochromes serve as circadian clock components and photoreceptors. Do DNA repair and circadian clock functions overlap in these flavoproteins? While 6-4 photolyase (6-4phr) is well-documented to repair UV-induced 6-4 photoproducts, we demonstrate that loss of 6-4phr function in fish cells and fin clips significantly attenuates circadian rhythms of period gene expression. Importantly, 6-4phr represses, as well as activates transcription directed by E-box and D-box enhancer elements respectively. Furthermore, we document physical interaction between 6-4phr and Clock1/Bmal1 at multiple domains which interferes with Clock1-Bmal1 heterodimerization. In addition, 6-4phr interacts with the D-box binding transcription factor, Tef. Thus, we reveal significant overlap between DNA repair and circadian clock functions in 6-4phr.
The Drosophila G protein-coupled receptor, GulpR, is essential for lipid mobilization in response to nutrient-limitation.
Barraza D, Ding X, Findley L … +3 more , Wang Z, Jugder BE, Watnick PI
PLoS Genet · 2025 Dec · PMID 41385596 · Full text
Enteroendocrine cells (EECs) of the intestinal epithelium are major regulators of metabolism and energy homeostasis. This is mainly due to their expression and secretion of enteroendocrine peptides (EEPs). These peptides...
Enteroendocrine cells (EECs) of the intestinal epithelium are major regulators of metabolism and energy homeostasis. This is mainly due to their expression and secretion of enteroendocrine peptides (EEPs). These peptides serve as hormones that control many aspects of metabolic homeostasis including feeding behavior, intestinal contractions, and utilization of energy stores. Regulation of EEP production and release depends largely on EEC-exclusive G protein-coupled receptors (GPCRs) that sense nutrient levels. Here we report the characterization of a GPCR expressed principally in EECs, which we have named GulpR due to its role in the response to nutrient stress. We show that GulpR regulates transcription of the EEP Tachykinin (Tk) and that both GulpR and Tk are essential for the transcriptional response that promotes survival of nutrient limitation. Oral infection with V. cholerae also activates expression of GulpR, Tk, and lipid mobilization genes. However, Tk does not play a role in regulation of lipid mobilization genes during infection and does not impact survival. Our findings identify a role for GulpR and Tk in survival during starvation and suggest that, although starvation and infection result in significant mobilization of energy stores, the signal transduction systems that regulate the metabolic response to each are distinct.
LIPL-1 and LIPL-2 are TCER-1-regulated lysosomal lipases with distinct roles in immunity and fertility.
Bahr L, Amrit FRG, Silvia PE … +11 more , Wayhs B, Osman GA, Devare MN, Henry H, Bui D, Choe M, Naim N, Champion M, Man Y, Olsen CP, Ghazi A
PLoS Genet · 2025 Dec · PMID 41385585 · Full text
Reproduction and immunity are energy intensive processes that often compete for resources, leading to trade-offs across species. Lipid metabolism integrates these processes, particularly during stressful conditions such...
Reproduction and immunity are energy intensive processes that often compete for resources, leading to trade-offs across species. Lipid metabolism integrates these processes, particularly during stressful conditions such as pathogenic infections, yet the underlying molecular mechanisms remain poorly understood. TCER-1, the C. elegans homolog of mammalian TCERG1, suppresses immunity and promotes fertility, especially upon maternal infection. Here, we show that TCER-1 coordinates this balance by regulating two conserved lysosomal lipases, lipl-1 and lipl-2. Using transcriptomic, lipidomic, and molecular-genetic analyses, we demonstrate that both lipases mediate infection-induced lipid remodeling but with distinct outcomes: lipl-1 promotes immunity, whereas, lipl-2 does not. LIPL-1 catalyzes the accumulation of specific ceramide species, including Cer 17:1;O2/24:0, whose supplementation rescues the immunity phenotypes of tcer-1;lipl-1 mutants and enhances post-infection survival of wild-type animals. Both lipases influence fertility with lipl-2 playing a key role in maintaining embryonic-eggshell integrity during maternal infection and aging. Remarkably, expression of human lysosomal acid lipase (hLAL/LIPA), the ortholog of 'lipl' genes, restores immunity defects triggered by lipl-1 loss and enhances immune resilience but does not significantly ameliorate the fertility defects. Together, these findings reveal distinct roles for lipl-1 and lipl-2 in modulating lipid species that link immune defense, reproductive fitness and healthspan through a potentially conserved mechanism.
The conserved SEN1 DNA/RNA helicase has multiple functions during yeast meiosis.
Gaglione R, Pierrakeas L, Wan L … +4 more , Caradonna J, MacQueen AJ, Luk E, Hollingsworth NM
PLoS Genet · 2025 Dec · PMID 41379861 · Full text
DNA:RNA hybrids are unusual structures found throughout the genomes of many species, including yeast and mammals. While DNA:RNA hybrids may promote various cellular functions, persistent hybrids lead to double strand bre...
DNA:RNA hybrids are unusual structures found throughout the genomes of many species, including yeast and mammals. While DNA:RNA hybrids may promote various cellular functions, persistent hybrids lead to double strand breaks, resulting in genomic instability. DNA:RNA hybrid formation and removal are therefore highly regulated, including by enzymes that either degrade or unwind RNA from the hybrid. Meiosis is the specialized cell division that creates haploid gametes for sexual reproduction. Previous work in yeast and mammals showed that elimination of DNA:RNA hybrids by RNase H facilitates meiotic recombination. This work demonstrates that the conserved Sen1 DNA/RNA helicase functions during three temporally distinct processes during yeast meiosis. First, SEN1 allows meiosis-specific genes to be expressed at the proper time to allow entry into meiosis. Second, SEN1 prevents the accumulation of hybrids during premeiotic DNA replication. Third, SEN1 promotes the repair of programmed meiotic double strand breaks that are necessary to form crossovers between homologous chromosomes to allow their proper segregation at the first meiotic division. Given the evolutionary conservation of Sen1 with its mammalian counterpart, Senataxin, studies of Sen1 function in yeast are likely to be informative about the regulation of DNA:RNA hybrids during human meiosis as well.
Exploiting peptide chirality and transport to dissect the complex mechanism of action of host peptides on bacteria.
Sankari S, Arnold MFF, Babu VMP … +2 more , Deutsch M, Walker GC
PLoS Genet · 2025 Dec · PMID 41379853 · Full text
Elucidation of the complex mechanisms of action of antimicrobial peptides (AMPs) is critical for improving their efficacy. A major challenge in AMP research is distinguishing AMP effects resulting from various protein in...
Elucidation of the complex mechanisms of action of antimicrobial peptides (AMPs) is critical for improving their efficacy. A major challenge in AMP research is distinguishing AMP effects resulting from various protein interactions from those caused by membrane disruption. Moreover, since AMPs often act in multiple cellular compartments, it is challenging to pinpoint where their distinct activities occur. Nodule-specific cysteine-rich (NCR) peptides secreted by some legumes, including NCR247, have evolved from AMPs to regulate differentiation of their nitrogen-fixing bacterial partner during symbiosis as well as to exert antimicrobial actions. At sub-lethal concentrations, NCR247 exhibits strikingly pleiotropic effects on Sinorhizobium meliloti. We used the L- and D-enantiomeric forms of NCR247 to distinguish between phenotypes resulting from stereospecific, protein-targeted interactions and those caused by non-specific interactions such as membrane disruption. In addition, we utilized an S. meliloti strain lacking BacA, a transporter that imports NCR peptides into the cytoplasm. The bacterial protein BacA, plays critical symbiotic roles by possibly reducing periplasmic peptide accumulation and fine-tuning symbiotic signaling. Use of the BacA-deficient strain made it possible to distinguish between phenotypes resulting from peptide interactions in the periplasm and those occurring in the cytoplasm. At high concentrations, both L- and D-NCR247 permeabilize bacterial membranes, consistent with nonspecific cationic AMP activity. In the cytoplasm, both NCR247 enantiomers sequester heme and trigger iron starvation in a chirality-independent but BacA-dependent manner. However, only L-NCR247 activates bacterial two-component systems via stereospecific periplasmic interactions. By combining stereochemistry and genetics, this work disentangles the spatial and molecular complexity of NCR247 action. This approach provides critical mechanistic insights into how host peptides with pleiotropic functions modulate bacterial physiology.
Aberrant cohesin function in Saccharomyces cerevisiae activates Mcd1 degradation to promote cell lethality.
Singh G, Skibbens RV
PLoS Genet · 2025 Dec · PMID 41370327 · Full text
The cohesin complex is composed of core ring proteins (Smc1, Smc3 and Mcd1) and associated factors (Pds5, Scc3, and Rad61) that bind via Mcd1. Extrusion (looping from within a single DNA molecule) and cohesion (the tethe...
The cohesin complex is composed of core ring proteins (Smc1, Smc3 and Mcd1) and associated factors (Pds5, Scc3, and Rad61) that bind via Mcd1. Extrusion (looping from within a single DNA molecule) and cohesion (the tethering together of two different DNA molecules) underlie the many roles that cohesins play in chromosome segregation, gene transcription, DNA repair, chromosome condensation, replication fork progression, and genome organization. While cohesin functions flank the activities of critical cell checkpoints (including spindle assembly and DNA damage checkpoints), the extent to which checkpoints directly target cohesins, in response to aberrant cohesin function, remains unknown. Based on prior evidence that cells mutated for cohesin contain reduced Mcd1 protein, we tested whether loss of Mcd1 is based simply on cohesin instability or integrity. The results show that Mcd1 loss persists even in rad61 cells, which contain elevated levels of stable chromosome-bound cohesins, and also in scc2-4, which do not affect cohesin complex integrity. In fact, re-elevating Mcd1 levels suppresses the temperature-sensitive growth defects of all cohesin alleles tested, revealing that Mcd1 loss is a fundamental mechanism through which cohesins are inactivated to promote cell lethality. Our findings further reveal that cells that exhibit aberrant cohesin function employ E3 ligases (such as San1) to target Mcd1 for degradation. This mechanism of degradation appears unique in that Mcd1 is reduced during S phase, when Mcd1 levels typically peak and despite a dramatic upregulation in MCD1 transcription. We infer from these latter findings that cells contain a negative feedback mechanism used to maintain Mcd1 homeostasis.
Endosymbiont hijacking of acylcarnitines regulates insect vector fecundity by suppressing the viability of stored sperm.
Weiss BL, Gstöttenmayer F, Awuoche E … +10 more , Smallenberger GM, Attardo GM, Scolari F, Koch RT, Bruzzese DJ, Echodu R, Opiro R, Malacrida A, Abd-Alla AMM, Aksoy S
PLoS Genet · 2025 Dec · PMID 41370310 · Full text
Competition between insects and their endosymbiotic bacteria for environmentally limited nutrients can compromise the fitness of both organisms. Tsetse flies, the vectors of pathogenic African trypanosomes, harbor a spec...
Competition between insects and their endosymbiotic bacteria for environmentally limited nutrients can compromise the fitness of both organisms. Tsetse flies, the vectors of pathogenic African trypanosomes, harbor a species and population-specific consortium of vertically transmitted endosymbiotic bacteria that range on the functional spectrum from mutualistic to parasitic. Tsetse's indigenous microbiota can include a member of the genus Spiroplasma, and infection with this bacterium causes fecundity-reducing phenotypes in the fly that include a prolonged gonotrophic cycle and a reduction in the motility of stored spermatozoa post-copulation. Herein we demonstrate that Spiroplasma and tsetse spermatozoa compete for fly-derived acylcarnitines, which in other bacteria and animals are used to maintain cell membranes and produce energy. The fat body of mated female flies increases acylcarnitine production in response to infection with Spiroplasma. Additionally, their spermathecae (sperm storage organs), and likely the sperm within, up-regulate expression of carnitine O-palmitoyltransferase-1, which is indicative of increased acylcarnitine metabolism and thus increased energy demand and energy production in this organ. These compensatory measures are insufficient to rescue the motility defect of spermatozoa stored in the spermathecae of Spiroplasma-infected females and thus results in reduced fly fecundity. Tsetse's taxonomically simple and highly tractable indigenous microbiota make the fly an efficient model system for studying the biological processes that facilitate the maintenance of bacterial endosymbioses, and how these relationships impact conserved mechanisms (mammalian spermatozoa also use acylcarnitines as an energy source) that regulated animal host fecundity. In the case of insect pests and vectors, a better understanding of the metabolic mechanisms that underlie these associations can lead to the development of novel control strategies.
ASNA1 is essential for cardiac development and function by regulating tail-anchored protein stability and vesicular transport in cardiomyocytes.
Feng W, Zhang Z, Chen Z … +6 more , Wang L, Ye M, Gu Y, Huang T, Ngo H, Chen J
PLoS Genet · 2025 Dec · PMID 41370295 · Full text
Recent studies have linked compound heterozygous mutations in ASNA1 to progressive dilated cardiomyopathy and early infantile mortality in humans. However, the specific role of ASNA1 in cardiomyocytes and the molecular m...
Recent studies have linked compound heterozygous mutations in ASNA1 to progressive dilated cardiomyopathy and early infantile mortality in humans. However, the specific role of ASNA1 in cardiomyocytes and the molecular mechanisms underlying ASNA1-related cardiomyopathy remain poorly understood. Tail-anchored (TA) proteins, characterized by a single C-terminal transmembrane domain (TMD), require post-translational targeting to intracellular membranes, a process primarily mediated by the evolutionarily conserved Guided Entry of Tail-anchored proteins (GET) pathway in yeast and the Transmembrane Recognition Complex (TRC) pathway in mammals. ASNA1 (also known as TRC40 or GET3) serves as the central ATP-dependent chaperone delivering TA proteins to the endoplasmic reticulum (ER) membrane. To address ASNA1's role in the heart, we generated constitutive and inducible cardiomyocyte-specific Asna1 knockout mouse models. Constitutive Asna1 deletion during embryogenesis caused perinatal lethality with marked ventricular myocardial thinning by embryonic day 16.5, whereas inducible deletion in adult cardiomyocytes led to rapid ventricular dilation, impaired cardiac function, pathological remodeling, and early mortality. Mechanistically, ASNA1 deficiency destabilized the pre-targeting complex and reduced the expression of multiple TA protein substrates, impairing membrane trafficking and protein transport. Transcriptomic analyses revealed compensatory upregulation of genes involved in protein trafficking and Golgi-to-ER transport, reflecting maladaptive responses to disrupted vesicular transport. Collectively, our findings identify ASNA1 as a critical regulator of TA protein stability and vesicular trafficking in cardiomyocytes, whose loss disrupts cardiac proteostasis and contributes to the cardiomyopathy pathogenesis. Our work provides mechanistic insights into ASNA1-related cardiac disease and highlights potential therapeutic targets.
Centromeres in budding yeasts are conserved in chromosomal location but not in structure.
Hession C, Byrne KP, Wolfe KH … +1 more , Butler G
PLoS Genet · 2025 Dec · PMID 41359681 · Full text
The budding yeast Saccharomyces cerevisiae has 'point' centromeres, which are much smaller and simpler than centromeres of most other eukaryotes and have a defined DNA sequence. Other yeast taxa have different and highly...
The budding yeast Saccharomyces cerevisiae has 'point' centromeres, which are much smaller and simpler than centromeres of most other eukaryotes and have a defined DNA sequence. Other yeast taxa have different and highly diverse centromere structures, but a clear picture of how yeast centromeres have evolved is lacking. Here, we investigated nine yeast species in two taxonomic orders that are close outgroups to S. cerevisiae. We find that they have a wide diversity of centromere structures, indicating that multiple transitions of structure have occurred within the last 200 Myr. Some species have centromeres with defined sequence motifs (17 - 200 bp), others consist of Inverted Repeats (IRs), and others have Ty5-like retroelement clusters. Strikingly, the chromosomal locations of centromeres have largely been conserved across taxonomic orders, even as their structures have changed, which suggests that structure replacement occurs in situ. In some Barnettozyma species we find that a single genome can contain chromosomes with different centromere structures - some with IRs and some without - which suggests that a structural transition is underway in this genus. We identified only one example of a centromere moving by a long distance: a new centromere formed recently at the MAT locus of Barnettozyma californica, 250 kb from the previous centromere on that chromosome.
A dendritic guidance receptor functions in both ligand dependent and independent modes.
Reddy AR, Machera SJ, Cook ZT … +4 more , Deng H, Nawrocka WI, Özkan E, Shen K
PLoS Genet · 2025 Dec · PMID 41348823 · Full text
The formation of an appropriately shaped dendritic arbor is critical for a neuron to receive information. Dendritic morphogenesis is a dynamic process involving growth, branching, and retraction. How the growth and stabi...
The formation of an appropriately shaped dendritic arbor is critical for a neuron to receive information. Dendritic morphogenesis is a dynamic process involving growth, branching, and retraction. How the growth and stabilization of dendrites are coordinated at the molecular level remains a key question in developmental neurobiology. The highly arborized and stereotyped dendritic arbors of the Caenorhabditis elegans PVD neuron are shaped by the transmembrane DMA-1 receptor through its interaction with a tripartite ligand complex consisting of SAX-7/L1CAM, MNR-1/FAM151B, and LECT-2/LECT2. However, receptor null mutants exhibit strongly reduced dendrite outgrowth, whereas ligand null mutants show disordered branch patterns, suggesting a ligand-independent function of the receptor. To test this idea, we identified point mutations in dma-1 that disrupt receptor-ligand binding and introduced corresponding mutations into the endogenous gene. We show that the ligand-free receptor is sufficient to drive robust, disordered dendritic branch formation but results in a complete loss of arbor shape. This disordered outgrowth program utilizes similar downstream effectors as the stereotyped outgrowth program, further arguing that ligand binding is not necessary for outgrowth. Finally, we demonstrate that ligand binding is required to maintain higher-order dendrites after development is complete. Taken together, our findings support a surprising model in which ligand-free and ligand-bound DMA-1 receptors have distinct functions: the ligand-free receptor promotes stochastic outgrowth and branching, whereas the ligand-bound receptor guides stereotyped dendrite morphology by stabilizing arbors at target locations.
Single-cell transcriptomics reveals stepwise transformation of epithelial cells into Non-Professional Phagocytes.
Almeida Machado Costa C, Santiago-Santiago CA, Huang YC … +1 more , Deng WM
PLoS Genet · 2025 Dec · PMID 41343490 · Full text
The differentiation of epithelial cells into Non-Professional Phagocytes (NPPs) is essential for maintaining tissue homeostasis and clearing apoptotic debris. In the Drosophila ovary, epithelial follicle cells transform...
The differentiation of epithelial cells into Non-Professional Phagocytes (NPPs) is essential for maintaining tissue homeostasis and clearing apoptotic debris. In the Drosophila ovary, epithelial follicle cells transform into NPPs following germline cell death, but the genetic mechanisms controlling this transition are not well defined. To investigate these mechanisms, we used a model in which overexpression of the active form of Notch, the Notch Intracellular Domain (NICD), induces a robust epithelial-to-NPP transition. Using single-cell RNA sequencing and trajectory analysis, we identified three transcriptional phases of NPP maturation: an early stage of metabolic activation, an intermediate stage enriched in genes related to migration and cytoskeletal remodeling, and a late stage marked by autophagy-related gene expression. These transcriptomic patterns were validated by immunostaining. SCENIC and ChiP-seq analyses identified the JNK effector Jun-related antigen (Jra) and its predicted targets, Arp2 and Arp3, which encode components of the Arp2/3 complex, as regulators of cytoskeletal remodeling. Functional assays confirmed that the JNK-Jra-Arp2/3 axis is required for cytoplasmic expansion and debris clearance during NPP differentiation.
Genomic evidence for a-α heterothallic and α-α unisexual mating and recombination in an environmental Cryptococcus deneoformans population.
Hitchcock M, Thorn V, Samarasinghe H … +3 more , Sun S, Heitman J, Xu J
PLoS Genet · 2025 Dec · PMID 41343430 · Full text
Cryptococcus deneoformans is a human fungal pathogen capable of both a-α and α-α mating and sexual reproduction in laboratory settings. However, the extent of a-α and α-α sexual reproductions in natural populations remai...
Cryptococcus deneoformans is a human fungal pathogen capable of both a-α and α-α mating and sexual reproduction in laboratory settings. However, the extent of a-α and α-α sexual reproductions in natural populations remain unexplored. Here we analyzed the whole-genome sequences of 24 environmental strains of C. deneoformans from western Saudi Arabia, including one MATa and 23 MATα isolates, with 15 MATα isolates belonging to multi-locus sequence type ST160 as defined by their combined DNA sequences at seven loci. To identify signatures for a-α and α-α reproduction, three samples were analyzed: total, MATα, and ST160. For each subpopulation, single nucleotide polymorphisms (SNPs) were identified for both the nuclear and mitochondrial genomes and subjected to four-gamete tests. In the total population and the MATα subpopulation, variable proportions of SNP pairs within as well as between the nuclear and the mitochondrial genomes showed evidence for recombination. Though no mitogenome SNPs were found among the 15 strains of ST160, the nuclear genome showed clear evidence for recombination, including among SNPs within the MATα mating type locus. In addition, the nuclear genome SNP pairs located further apart on the same chromosome showed a greater frequency of recombination in all three sample types. In contrast, mitogenome SNPs involved in recombination were mainly located in two large genomic regions. Together, these results provide robust evidence for both a-α and α-α sexual reproduction within this environmental population of C. deneoformans.
Unraveling forensic timelines using molecular markers in Phormia regina maggots.
Lin SH, Bellantuono AJ, Lopez K … +2 more , Wells JD, DeGennaro M
PLoS Genet · 2025 Dec · PMID 41343428 · Full text
In the medico-legal application of forensic entomology, estimating the time of death is critical and traditionally relies on changes in observable traits of carrion feeding insect larvae. Traits such as size, weight, and...
In the medico-legal application of forensic entomology, estimating the time of death is critical and traditionally relies on changes in observable traits of carrion feeding insect larvae. Traits such as size, weight, and morphology can be used to predict the insect specimen age and help define the minimum time since death. The blowfly Phormia regina Meigen (Diptera: Calliphoridae) is a key forensic insect, yet age estimation for older maggots in this and other carrion-feeding species is particularly challenging due to the limited morphological changes in the late-stage larvae. To enhance age-estimation precision, we employed transcriptomic profiling on blowfly maggots, aiming to identify genes as markers for time of death estimation. Our study characterized maggot development, reinforcing that weight and behavior cannot precisely determine age between 100 and 130 hours at 27.5 °C. We built a chromosomal scale annotated genome, establishing a reliable database for uncovering transcriptomic signatures during larval development. Applying differential gene expression analyses, weighted gene co-expression network analysis, and the generalized linear model, we identified nine candidate genes (y5078, y5076, agt2, ech1, dhb4, asm, gabd, acohc, ivd) that delineate the age of otherwise indeterminate maggots. This research introduces a molecular approach to address a longstanding problem in forensic entomology and promises to increase precision in determining the time of death at a crime scene.
A fly model of SCA36 reveals combinatorial neurotoxicity of hexanucleotide and dipeptide repeats.
Hsiao CT, Fu SJ, Guo TN … +9 more , Lin CC, Tsao YJ, Chang W, Liao YC, Hashimoto M, Huang SY, Lee YC, Yu CH, Chan CC
PLoS Genet · 2025 Dec · PMID 41337098 · Full text
Spinocerebellar ataxia type 36 (SCA36) is a neurodegenerative disease caused by expanded (GGCCTG)n hexanucleotide repeat sequence in the NOP56 gene. While the expanded repeats could transcribe and form toxic RNA foci wit...
Spinocerebellar ataxia type 36 (SCA36) is a neurodegenerative disease caused by expanded (GGCCTG)n hexanucleotide repeat sequence in the NOP56 gene. While the expanded repeats could transcribe and form toxic RNA foci within neurons, recent evidence indicates that translation of these repeats produces dipeptide repeats (DPR) that contribute to neurotoxicity. The relative impact of hexanucleotide RNA repeats (HRR) and DPR on the neurodegeneration of SCA36 remains unclear. Here, we established a Drosophila SCA36 model to dissect the neurotoxic effects of HRR and DPR. The fly model recapitulates the cellular defects observed in SCA36 patient fibroblasts, validating its relevance for mechanistic study of SCA36. Further engineering the transgenes to express individual DPRs reveal Proline-Glycine-DPR (PG-DPR) as the most potent neurotoxin causing progressive motor and sensory dysfunction. Expressing a series of the SCA36 transgenes with varying HRR lengths demonstrates an age- and length-dependent adult-onset neurodegeneration. Interestingly, sequence modification of the transgenes to exclusively express HRR or DPR alone causes a milder phenotype, indicating both HRR and DPR contribute partially to the pathogenicity of SCA36. Therefore, this model provides a valuable platform for screening drug targeting either HRR- or DPR-mediated toxicity of SCA36. Suppression of the RNA elongation factor SUPT4H1 ortholog reduces RNA foci in cell culture. However, expression level of SUPT4H1 was not changed in SCA36 patient cells. Interestingly, knockdown of the Drosophila SUPT4H1 ortholog or 6-azauridine treatment to suppress RNA transcription aggravates the neurodegenerative phenotypes in both the fly models and patient-derived fibroblasts, highlighting the complex interplay of pathomechanisms in SCA36. These results underscore the need for carefully evaluating the potential side effects when designing therapeutic interventions for SCA36.
Early life starvation and Hedgehog-related signaling activate innate immunity downstream of daf-18/PTEN and lin-35/Rb causing developmental pathology in adult C. elegans.
Falsztyn IB, Jordan JM, Chen J … +4 more , Zhao W, Chitrakar R, Reinke AW, Baugh LR
PLoS Genet · 2025 Dec · PMID 41336845 · Full text
Early life experiences such as malnutrition can affect development and adult disease risk, but the molecular basis of such protracted effects is poorly understood. In the nematode C. elegans, extended starvation during t...
Early life experiences such as malnutrition can affect development and adult disease risk, but the molecular basis of such protracted effects is poorly understood. In the nematode C. elegans, extended starvation during the first larval stage causes the development of germline tumors and other abnormalities in the adult gonad, limiting reproductive success. Insulin/IGF signaling (IIS) acts through WNT signaling and lipid metabolism to promote starvation-induced gonad abnormalities, but IIS-independent modifiers have not been identified. The tumor suppressor daf-18/PTEN inhibits IIS to suppress starvation-induced abnormalities, but we show that it also acts independently of IIS via lin-35/Rb, another tumor suppressor, to suppress such abnormalities. We found that lin-35/Rb and the rest of the DREAM complex repress transcription of the Hedgehog (Hh) signaling homologs ptr-23/PTCH-related, wrt-1/Hh-like, and wrt-10/Hh-like, which promote starvation-induced abnormalities. These Hh-related genes transcriptionally activate several genes associated with innate immunity in adults, which also promote starvation-induced gonad abnormalities. Surprisingly, we found that in addition to causing developmental abnormalities, early-life starvation induces an innate immune response later in life, leading to increased resistance to bacterial and intracellular pathogens. This work identifies a critical tumor-suppressor function of daf-18/PTEN independent of IIS, and it defines a regulatory network, including lin-35/Rb and DREAM, Hh-related signaling, and innate immunity pathways, that affects development of tumors and other developmental abnormalities resulting from early life starvation. By revealing that early-life starvation increases immunity later in life, this work suggests a fitness tradeoff between pathogen resistance and developmental robustness.
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