IF 6.4 1区生物学

eLife Pub Date : 2026-10-09 DOI: 10.7554/eLife.109450

Anna G Green, Mahbuba Tasmin, Roger Vargas, Maha Reda Farhat

{"title":"The structural context of mutations in proteins predicts their effect on antibiotic resistance.","authors":"Anna G Green, Mahbuba Tasmin, Roger Vargas, Maha Reda Farhat","doi":"10.7554/eLife.109450","DOIUrl":"10.7554/eLife.109450","url":null,"abstract":"In Mycobacterium tuberculosis, a prevalent and deadly pathogen, resistance to antibiotics evolves primarily through non-synonymous mutations in proteins. Sequence-based analyses can uncover the genetic basis of antibiotic resistance, but these methods focus on primary sequence and often neglect other biological signals, such as protein structural information. We hypothesize that integrating the structural context of mutations improves the prediction of effects on function and phenotype. We curate high-confidence structural annotations for the M. tuberculosis proteome from 1350 crystallography and 2337 AlphaFold predictions, and mutations from over 31,000 M. tuberculosis isolates. We demonstrate that mutations in proteins known to cause resistance are clustered in 3D space, even in proteins where inactivating mutations at any position are thought to cause resistance. We find over 450 proteins in the M. tuberculosis proteome that display signals of clustered mutations, many of which have a known relationship with antibiotic resistance. We show that a supervised classifier trained on 3D distance to known resistance sites alone has an F1 score of 96.5% at classifying mutations as resistance-conferring on a held-out test set. This work demonstrates that protein structure provides useful information for categorizing which variants may cause antibiotic resistance, even when the majority of structures are AI-predicted.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Obtaining maximum information from colony counts with REPOP. 用REPOP从菌落计数中获得最大的信息。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-09 DOI: 10.7554/eLife.107122

Pedro Pessoa, Carol Yunxiao Slayton, Stanimir Asenov Tashev, Rory Kruithoff, Doug P Shepherd, Steve Presse

{"title":"Obtaining maximum information from colony counts with REPOP.","authors":"Pedro Pessoa, Carol Yunxiao Slayton, Stanimir Asenov Tashev, Rory Kruithoff, Doug P Shepherd, Steve Presse","doi":"10.7554/eLife.107122","DOIUrl":"10.7554/eLife.107122","url":null,"abstract":"Bacterial counts from native environments, such as soil or the animal gut, often show substantial variability across replicate samples. This heterogeneity is typically attributed to genetic or environmental factors. A common approach to estimating bacterial populations involves successive dilution and plating, followed by multiplying colony counts by dilution factors. This method, however, overestimates the heterogeneity in bacterial population because it conflates the inherent uncertainty in drawing a subsample from the total population with the uncertainty in the sample arising from biological origins. In other words, this approach may obscure features that may otherwise be present in the data, hinting at the presence of genuine subpopulations. For example, in plate counting applied to Caenorhabditis elegans gut microbiota, observed multimodality is often interpreted as large host-to-host variance, while the randomness introduced by measurement is frequently ignored. To explicitly account for the uncertainty introduced by dilution and plating randomness, we introduce REPOP, a PyTorch-based library to REconstruct POpulations from Plates within a Bayesian framework. Beyond simple cases, REPOP addresses more complex scenarios, including multimodal populations and correcting the mathematically subtle, but experimentally relevant, bias introduced by excluding plates deemed too crowded to distinguish individual colonies. We demonstrate REPOP's ability to resolve distinct population peaks otherwise obscured by standard multiplication methods. Applications to both simulated and experimental datasets, including bacterial samples of different concentrations and ones from the gut microbiota of C. elegans, show that REPOP accurately recovers the underlying multimodality by properly accounting for error propagation, where naive multiplication fails. REPOP is available on GitHub: https://github.com/LabPresse/REPOP.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Punctuated mutagenesis promotes multi-step evolutionary adaptation in human cancers. 间断突变促进了人类癌症的多步进化适应。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-09 DOI: 10.7554/eLife.108058

Christopher J Graser, Wenbo Wu, Cole Christini, Mia Peljak, Franziska Michor

{"title":"Punctuated mutagenesis promotes multi-step evolutionary adaptation in human cancers.","authors":"Christopher J Graser, Wenbo Wu, Cole Christini, Mia Peljak, Franziska Michor","doi":"10.7554/eLife.108058","DOIUrl":"10.7554/eLife.108058","url":null,"abstract":"The rate of acquisition of genomic changes in cancer has been the topic of much discussion, with several recent investigations finding evidence of punctuated evolution instead of gradual accumulation of such changes. Despite forays into the description and quantification of these punctuated events, the effects of such changes on subsequent cancer evolution remain incompletely understood. Here we investigate how non-gradual mutagenesis affects the ability of tumor cells to acquire and retain fitness-enhancing adaptations. We find that punctuated mutagenesis significantly facilitates adaptation in scenarios where adaptation requires crossing a fitness valley, that is when multiple mutations are required which individually are maladaptive but jointly confer a fitness advantage. By increasing the probability that multiple mutations occur in close succession, punctuation increases the chance that mutants in a fitness valley mutate further to reach a fitness peak before going extinct. Analyzing data from The Cancer Genome Atlas, we find that tumors with signatures of APOBEC mutagenesis, which has been shown to proceed in episodic bursts, exhibit patterns consistent with higher rates of crossing fitness valleys. Lastly, we characterize how the interplay between this enhanced ability to cross fitness valleys and adaptation-limiting effects of clonal interference affects overall adaptability in complex fitness landscapes.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Starvation transforms signal encoding in C. elegans thermoresponsive neurons and suppresses heat avoidance via bidirectional glutamatergic and peptidergic signaling. 饥饿改变线虫热反应神经元的信号编码，并通过双向谷氨酸能和肽能信号传导抑制热回避。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-09 DOI: 10.7554/eLife.108246

Saurabh Thapliyal, Parvathi Sushama Gopinath, Dominique A Glauser

{"title":"Starvation transforms signal encoding in C. elegans thermoresponsive neurons and suppresses heat avoidance via bidirectional glutamatergic and peptidergic signaling.","authors":"Saurabh Thapliyal, Parvathi Sushama Gopinath, Dominique A Glauser","doi":"10.7554/eLife.108246","DOIUrl":"10.7554/eLife.108246","url":null,"abstract":"Animals must continuously adapt their behavioral outputs in response to changes in internal state, including nutritional state. Here, we show that starvation induces a profound and progressive suppression of thermonociceptive behavior in Caenorhabditis elegans. During early food deprivation (1 hr without food), the thermoresponsive AWC sensory neurons mediate robust heat-evoked reversals over a broad range of stimulus intensities via glutamate and FLP-6 neuropeptide signaling, each covering distinct heat intensity ranges. After 6 hr of food deprivation (prolonged starvation), heat-evoked reversal responses are nearly abolished, independently of external food odor cues. Starvation shifts the distribution of AWC heat-evoked calcium response polarity, from mostly excitatory responses to a heterogeneous pattern combining excitatory and inhibitory activities. This switch relies on ASI neurons, proposed to sense internal state. INS-32 and NLP-18 neuropeptide signals from ASI switch from reversal-promoting to reversal-inhibiting effects. In addition, reversal-promoting glutamatergic transmission by AWC is antagonized by glutamatergic transmission from non-AWC neurons that suppress FLP-6-dependent reversals. Our findings define a circuit logic by which gating of nociceptive responsiveness by internal nutritional state is linked to dynamic modulation of sensory neuron activity patterns and orchestrated by bidirectional glutamatergic and neuropeptidergic signals.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of desolvation on biomolecular liquid-liquid phase separation. 溶解在生物分子液-液相分离中的作用。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-09 DOI: 10.7554/eLife.111124

Kai Zhang, Zhiyu Peng, Wenfei Li, Wei Wang

{"title":"Role of desolvation on biomolecular liquid-liquid phase separation.","authors":"Kai Zhang, Zhiyu Peng, Wenfei Li, Wei Wang","doi":"10.7554/eLife.111124","DOIUrl":"10.7554/eLife.111124","url":null,"abstract":"Biomolecular condensates play essential roles in cellular organization and are implicated in diverse pathological processes. Their formation is driven by liquid-liquid phase separation (LLPS), a process that requires coordinated multistep desolvation of biomolecular chains and multivalent inter-chain interactions. Although coarse-grained (CG) models with implicit solvent are widely used to probe LLPS thermodynamics and kinetics, they typically neglect water-mediated desolvation effects, limiting their accuracy and mechanistic interpretability. Here, guided by all-atom simulations and experimental measurements, we develop a desolvation-aware implicit-solvent CG model by incorporating residue-level desolvation terms directly into the pairwise energy function, and apply it to investigate LLPS of intrinsically disordered proteins. Incorporating these desolvation interactions reshapes the phase diagram, alleviating dense-phase overcompaction. Notably, we observe an approximately linear correlation between the temperature gap (simulation temperature relative to the critical point) and the extent of conformational expansion accompanying the dilute-to-dense phase transition, a result further supported by theoretical analysis. We also find that desolvation barriers slow early density-fluctuation growth and shorten transient kinetic arrest, whereas solvent-separated contact interactions exert the opposite effects. Both terms further modulate chain mobility within mature condensates through competing packing and energy-landscape effects. Together, this framework enables an efficient representation of desolvation in CG simulations and reveals how desolvation energetics shape both the thermodynamic landscape and kinetic properties of biomolecular LLPS.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolism. SIRT4的光下调通过脂肪酸代谢增强H3K9ac来减缓小鼠衰老。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-08 DOI: 10.7554/eLife.111498

Fangqing Deng, Rong Yang, Jinyun Niu, Monian Wang, Yang Liu, Xu Li, Zibo Gao, Lihua Yang, Huifang Liu, Yingchun Yang, Zhaoxiang Yu, Lianbing Zhang

{"title":"Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolism.","authors":"Fangqing Deng, Rong Yang, Jinyun Niu, Monian Wang, Yang Liu, Xu Li, Zibo Gao, Lihua Yang, Huifang Liu, Yingchun Yang, Zhaoxiang Yu, Lianbing Zhang","doi":"10.7554/eLife.111498","DOIUrl":"10.7554/eLife.111498","url":null,"abstract":"As organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase, a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and the TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR-α in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Early recruitment of membrane-bound DNaseX to phagocytic cups in macrophages. 巨噬细胞吞噬杯中早期膜结合DNaseX的募集。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-08 DOI: 10.7554/eLife.110907

Arghajit Pyne, Vivek Pandey, Subhankar Kundu, Sachie Ikegami, Xuefeng Wang

{"title":"Early recruitment of membrane-bound DNaseX to phagocytic cups in macrophages.","authors":"Arghajit Pyne, Vivek Pandey, Subhankar Kundu, Sachie Ikegami, Xuefeng Wang","doi":"10.7554/eLife.110907","DOIUrl":"10.7554/eLife.110907","url":null,"abstract":"Macrophages engulf and degrade pathogens and cellular debris through phagocytosis. The degradation process was generally believed to occur only after phagosome internalization and maturation. Here, we report an early DNase activity at the nascent phagocytic cup (PC) prior to its closure. Using a fluorescent DNase sensor, we revealed rapid and ubiquitous DNase activity upon PC formation across various macrophage types. We further identified the responsible enzyme as the membrane-bound DNaseX, which is constitutively recruited to the PC during PC formation. F-actin polymerization was found to correlate with DNase activity in the PC, likely by promoting physical engagement of DNaseX with solid DNA materials. Functionally, we show that macrophages degrade extracellular DNA (eDNA) within bacterial biofilms through direct physical contact, clearing the eDNA structures without internalization. These findings reveal a previously unrecognized DNA degradation mechanism operating at the macrophage membrane, suitable for degrading bulky eDNA materials which cannot be directly internalized by macrophages.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome-wide synthetic lethality screen of Bam complex-associated genes in Escherichia coli. 大肠杆菌Bam复合物相关基因的全基因组合成致死性筛选。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-08 DOI: 10.7554/eLife.99955

Jack A Bryant, Kara A Staunton, Hannah M Doherty, Micheal B Alao, Xuyu Ma, Joanna Morcinek-Orlowska, Emily C A Goodall, Jessica Gray, Matthew Milner, Luke Kidger, Charly D Neilson, Jeffrey A Cole, Felicity de Cogan, Timothy J Knowles, Monika Glinkowska, Danesh Moradigaravand, Ian R Henderson, Manuel Banzhaf

{"title":"Genome-wide synthetic lethality screen of Bam complex-associated genes in Escherichia coli.","authors":"Jack A Bryant, Kara A Staunton, Hannah M Doherty, Micheal B Alao, Xuyu Ma, Joanna Morcinek-Orlowska, Emily C A Goodall, Jessica Gray, Matthew Milner, Luke Kidger, Charly D Neilson, Jeffrey A Cole, Felicity de Cogan, Timothy J Knowles, Monika Glinkowska, Danesh Moradigaravand, Ian R Henderson, Manuel Banzhaf","doi":"10.7554/eLife.99955","DOIUrl":"10.7554/eLife.99955","url":null,"abstract":"Biogenesis of the bacterial outer membrane is key to bacterial survival and antibiotic resistance. Central to this is the β-barrel assembly machine (Bam) complex and its associated chaperones, which are responsible for transport, folding, and insertion of outer membrane proteins (OMPs). The Escherichia coli Bam complex is composed of two essential subunits, BamA and BamD, and three non-essential accessory lipoproteins, BamB, BamC, and BamE. Optimal Bam function is further dependent on the non-essential periplasmic chaperones DegP, Skp, and SurA. Despite intensive study, the specific function of these non-essential Bam-associated proteins is not fully understood. Here, we analysed ΔbamB, ΔbamC, ΔbamE, ΔsurA, Δskp, and ΔdegP knockout strains by phenotypic screening, conservation analysis and high-throughput genetics. We identified hundreds of synthetic-lethal interactions and revealed that Bam complex activity is impacted by changes in outer membrane lipid composition and that enterobacterial common antigen is essential in the absence of the chaperone SurA. We also show that genes responsible for synthesis of peptidoglycan are synthetically lethal with Bam accessory lipoprotein encoding genes. Together, our data indicate potential mechanisms for coordination of OMP biogenesis with other cellular growth processes, such as LPS and peptidoglycan biogenesis.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Circadian photoreceptor CRYPTOCHROME promotes wakefulness under short winter-like days via a GABAergic circuitry. 昼夜节律光感受器CRYPTOCHROME通过gaba能电路促进在短的冬季样的日子清醒。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-08 DOI: 10.7554/eLife.92608

Lixia Chen, Danya Tian, Chang Su, Luoying Zhang

{"title":"Circadian photoreceptor CRYPTOCHROME promotes wakefulness under short winter-like days via a GABAergic circuitry.","authors":"Lixia Chen, Danya Tian, Chang Su, Luoying Zhang","doi":"10.7554/eLife.92608","DOIUrl":"10.7554/eLife.92608","url":null,"abstract":"A cardinal symptom of seasonal affective disorder (SAD, also known as winter depression) is hypersomnolence, while the cause of this 'winter sleepiness' is not known. Here, we found that lack of the circadian photoreceptor cryptochrome (cry) leads to increased sleep under short winter-like days in the fruit fly Drosophila, reminiscent of the hypersomnolence in SAD. CRY functions in neurons that synthesize the major inhibitory neurotransmitter GABA, including the small ventral lateral neurons, which are known to be circadian pacemakers, and downregulates the GABAergic tone. This, in turn, leads to increased neural activity of the wake-promoting large ventral lateral neurons, a subset of circadian neurons that are inhibited by GABA-A receptors. CRY protein is known to be degraded by light, thus rendering CRY to be functional within this GABAergic circuitry to enhance wakefulness only under short-day length. Taken together, we demonstrate a mechanism that specifically regulates wakefulness under short winter-like days, which may provide insights regarding the winter sleepiness in SAD.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Heterogeneity and ontogeny of mouse thymic macrophages reveal a requirement for Csf1r-expressing myeloid cells during early T cell development. 小鼠胸腺巨噬细胞的异质性和个体发生揭示了在早期T细胞发育过程中对表达csf1r的骨髓细胞的需求。

IF 6.4 1区生物学

eLife Pub Date : 2026-10-07 DOI: 10.7554/eLife.109219

Helen Wang, Vinothkumar Rajan, Anthony Wong, Slava Epelman, Juan Carlos Zúñiga-Pflücker

{"title":"Heterogeneity and ontogeny of mouse thymic macrophages reveal a requirement for Csf1r-expressing myeloid cells during early T cell development.","authors":"Helen Wang, Vinothkumar Rajan, Anthony Wong, Slava Epelman, Juan Carlos Zúñiga-Pflücker","doi":"10.7554/eLife.109219","DOIUrl":"10.7554/eLife.109219","url":null,"abstract":"Thymic macrophages (TMs) maintain tissue homeostasis by clearing the large numbers of apoptotic cells generated during T cell development, but how TM heterogeneity relates to their developmental origin and role in thymocyte maturation remains incompletely understood. Using complementary flow-cytometric, single-cell transcriptomic, and genetic approaches, we resolved two major TM populations corresponding to TIMD4+ cortical and CX3CR1+ medullary/cortico-medullary macrophages. TIMD4+ VCAM1+ TMs displayed a prominent efferocytosis and apoptotic-cell-clearance program, whereas TIMD4- VCAM1+ TMs were enriched for antigen-presentation and interferon-response pathways. Fate mapping revealed unequal progenitor contributions to these populations, and CCR2 deficiency selectively reduced TIMD4- VCAM1+ TMs, and thymic monocytes, supporting ongoing input from circulating precursors. Exploratory pseudotime analysis further identified a transcriptional continuum from Ly6c2+Ccr2+ monocytes toward macrophage states. Using MaFIA fetal thymic organ cultures, AP20187-mediated depletion of Csf1r-expressing myeloid cells reduced CD4+CD8+ thymocyte differentiation and produced a coordinated accumulation of DN3 cells, loss of DN4 cells, and reduction in CD27 expression. These convergent changes identify the DN3-to-DN4 transition as a developmental stage that requires an intact Csf1r-expressing myeloid compartment and establish a functional connection between the thymic myeloid niche and early αβ T cell development. Together, our study refines the phenotypic and developmental organization of mouse TMs and reveals a previously underappreciated requirement for myeloid-cell support during progression through the β-selection checkpoint.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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