eLife最新文献_第9页

A microglia clonal inflammatory disorder in Alzheimer's disease.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.96519

Rocio Vicario, Stamatina Fragkogianni, Leslie Weber, Tomi Lazarov, Yang Hu, Samantha Y Hayashi, Barbara Craddock, Nicholas D Socci, Araitz Alberdi, Ann Baako, Oyku Ay, Masato Ogishi, Estibaliz Lopez-Rodrigo, Rajya Kappagantula, Agnes Viale, Christine A Iacobuzio-Donahue, Ting Zhou, Richard M Ransohoff, Richard Chesworth, Omar Abdel-Wahab, Bertrand Boisson, Olivier Elemento, Jean-Laurent Casanova, W Todd Miller, Frédéric Geissmann

{"title":"A microglia clonal inflammatory disorder in Alzheimer's disease.","authors":"Rocio Vicario, Stamatina Fragkogianni, Leslie Weber, Tomi Lazarov, Yang Hu, Samantha Y Hayashi, Barbara Craddock, Nicholas D Socci, Araitz Alberdi, Ann Baako, Oyku Ay, Masato Ogishi, Estibaliz Lopez-Rodrigo, Rajya Kappagantula, Agnes Viale, Christine A Iacobuzio-Donahue, Ting Zhou, Richard M Ransohoff, Richard Chesworth, Omar Abdel-Wahab, Bertrand Boisson, Olivier Elemento, Jean-Laurent Casanova, W Todd Miller, Frédéric Geissmann","doi":"10.7554/eLife.96519","DOIUrl":"10.7554/eLife.96519","url":null,"abstract":"Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer's disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630310","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

Receptor tyrosine kinases CAD96CA and FGFR1 function as the cell membrane receptors of insect juvenile hormone.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.97189

Yan-Xue Li, Xin-Le Kang, Yan-Li Li, Xiao-Pei Wang, Qiao Yan, Jin-Xing Wang, Xiao-Fan Zhao

引用次数: 0

Microprism-based two-photon imaging of the mouse inferior colliculus reveals novel organizational principles of the auditory midbrain.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.93063

Baher A Ibrahim, Yoshitaka Shinagawa, Austin Douglas, Gang Xiao, Alexander R Asilador, Daniel A Llano

{"title":"Microprism-based two-photon imaging of the mouse inferior colliculus reveals novel organizational principles of the auditory midbrain.","authors":"Baher A Ibrahim, Yoshitaka Shinagawa, Austin Douglas, Gang Xiao, Alexander R Asilador, Daniel A Llano","doi":"10.7554/eLife.93063","DOIUrl":"10.7554/eLife.93063","url":null,"abstract":"To navigate real-world listening conditions, the auditory system relies on the integration of multiple sources of information. However, to avoid inappropriate cross-talk between inputs, highly connected neural systems need to strike a balance between integration and segregation. Here, we develop a novel approach to examine how repeated neurochemical modules in the mouse inferior colliculus lateral cortex (LC) allow controlled integration of its multimodal inputs. The LC had been impossible to study via imaging because it is buried in a sulcus. Therefore, we coupled two-photon microscopy with the use of a microprism to reveal the first-ever sagittal views of the LC to examine neuronal responses with respect to its neurochemical motifs under anesthetized and awake conditions. This approach revealed marked differences in the acoustic response properties of LC and neighboring non-lemniscal portions of the inferior colliculus. In addition, we observed that the module and matrix cellular motifs of the LC displayed distinct somatosensory and auditory responses. Specifically, neurons in modules demonstrated primarily offset responses to acoustic stimuli with enhancement in responses to bimodal stimuli, whereas matrix neurons showed onset response to acoustic stimuli and suppressed responses to bimodal stimulation. Thus, this new approach revealed that the repeated structural motifs of the LC permit functional integration of multimodal inputs while retaining distinct response properties.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630323","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

Gaskell, Langley, and the "para-sympathetic" idea.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.104826

Jean-François Brunet

引用次数: 0

Dual role of FOXG1 in regulating gliogenesis in the developing neocortex via the FGF signalling pathway.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.101851

Mahima Bose, Ishita Talwar, Varun Suresh, Urvi Mishra, Shiona Biswas, Anuradha Yadav, Shital T Suryavanshi, Simon Hippenmeyer, Shubha Tole

{"title":"Dual role of FOXG1 in regulating gliogenesis in the developing neocortex via the FGF signalling pathway.","authors":"Mahima Bose, Ishita Talwar, Varun Suresh, Urvi Mishra, Shiona Biswas, Anuradha Yadav, Shital T Suryavanshi, Simon Hippenmeyer, Shubha Tole","doi":"10.7554/eLife.101851","DOIUrl":"10.7554/eLife.101851","url":null,"abstract":"In the developing vertebrate central nervous system, neurons and glia typically arise sequentially from common progenitors. Here, we report that the transcription factor Forkhead Box G1 (Foxg1) regulates gliogenesis in the mouse neocortex via distinct cell-autonomous roles in progenitors and postmitotic neurons that regulate different aspects of the gliogenic FGF signalling pathway. We demonstrate that loss of Foxg1 in cortical progenitors at neurogenic stages causes premature astrogliogenesis. We identify a novel FOXG1 target, the pro-gliogenic FGF pathway component Fgfr3, which is suppressed by FOXG1 cell-autonomously to maintain neurogenesis. Furthermore, FOXG1 can also suppress premature astrogliogenesis triggered by the augmentation of FGF signalling. We identify a second novel function of FOXG1 in regulating the expression of gliogenic cues in newborn neocortical upper-layer neurons. Loss of FOXG1 in postmitotic neurons non-autonomously enhances gliogenesis in the progenitors via FGF signalling. These results fit well with the model that newborn neurons secrete cues that trigger progenitors to produce the next wave of cell types, astrocytes. If FGF signalling is attenuated in Foxg1 null progenitors, they progress to oligodendrocyte production. Therefore, loss of FOXG1 transitions the progenitor to a gliogenic state, producing either astrocytes or oligodendrocytes depending on FGF signalling levels. Our results uncover how FOXG1 integrates extrinsic signalling via the FGF pathway to regulate the sequential generation of neurons, astrocytes, and oligodendrocytes in the cerebral cortex.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630312","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

Expression of a single inhibitory member of the Ly49 receptor family is sufficient to license NK cells for effector functions.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.100218

Sytse J Piersma, Shasha Li, Pamela Wong, Michael D Bern, Jennifer Poursine-Laurent, Liping Yang, Diana L Beckman, Bijal A Parikh, Wayne M Yokoyama

{"title":"Expression of a single inhibitory member of the Ly49 receptor family is sufficient to license NK cells for effector functions.","authors":"Sytse J Piersma, Shasha Li, Pamela Wong, Michael D Bern, Jennifer Poursine-Laurent, Liping Yang, Diana L Beckman, Bijal A Parikh, Wayne M Yokoyama","doi":"10.7554/eLife.100218","DOIUrl":"10.7554/eLife.100218","url":null,"abstract":"Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on an H-2Dd background restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630316","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

Nuclear Argonaute protein NRDE-3 switches small RNA partners during embryogenesis to mediate temporal-specific gene regulatory activity.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-13 DOI: 10.7554/eLife.102226

Shihui Chen, Carolyn Marie Phillips

{"title":"Nuclear Argonaute protein NRDE-3 switches small RNA partners during embryogenesis to mediate temporal-specific gene regulatory activity.","authors":"Shihui Chen, Carolyn Marie Phillips","doi":"10.7554/eLife.102226","DOIUrl":"10.7554/eLife.102226","url":null,"abstract":"RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623920","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

Exploring the repository of de novo-designed bifunctional antimicrobial peptides through deep learning.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-13 DOI: 10.7554/eLife.97330

Ruihan Dong, Rongrong Liu, Ziyu Liu, Yangang Liu, Gaomei Zhao, Honglei Li, Shiyuan Hou, Xiaohan Ma, Huarui Kang, Jing Liu, Fei Guo, Ping Zhao, Junping Wang, Cheng Wang, Xingan Wu, Sheng Ye, Cheng Zhu

{"title":"Exploring the repository of de novo-designed bifunctional antimicrobial peptides through deep learning.","authors":"Ruihan Dong, Rongrong Liu, Ziyu Liu, Yangang Liu, Gaomei Zhao, Honglei Li, Shiyuan Hou, Xiaohan Ma, Huarui Kang, Jing Liu, Fei Guo, Ping Zhao, Junping Wang, Cheng Wang, Xingan Wu, Sheng Ye, Cheng Zhu","doi":"10.7554/eLife.97330","DOIUrl":"10.7554/eLife.97330","url":null,"abstract":"Antimicrobial peptides (AMPs) are attractive candidates to combat antibiotic resistance for their capability to target biomembranes and restrict a wide range of pathogens. It is a daunting challenge to discover novel AMPs due to their sparse distributions in a vast peptide universe, especially for peptides that demonstrate potencies for both bacterial membranes and viral envelopes. Here, we establish a de novo AMP design framework by bridging a deep generative module and a graph-encoding activity regressor. The generative module learns hidden 'grammars' of AMP features and produces candidates sequentially pass antimicrobial predictor and antiviral classifiers. We discovered 16 bifunctional AMPs and experimentally validated their abilities to inhibit a spectrum of pathogens in vitro and in animal models. Notably, P076 is a highly potent bactericide with the minimal inhibitory concentration of 0.21 μM against multidrug-resistant Acinetobacter baumannii, while P002 broadly inhibits five enveloped viruses. Our study provides feasible means to uncover the sequences that simultaneously encode antimicrobial and antiviral activities, thus bolstering the function spectra of AMPs to combat a wide range of drug-resistant infections.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623913","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

Protein absorption in the zebrafish gut is regulated by interactions between lysosome rich enterocytes and the microbiome.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-13 DOI: 10.7554/eLife.100611

Laura Childers, Jieun Park, Siyao Wang, Richard Liu, Robert Barry, Stephen A Watts, John F Rawls, Michel Bagnat

{"title":"Protein absorption in the zebrafish gut is regulated by interactions between lysosome rich enterocytes and the microbiome.","authors":"Laura Childers, Jieun Park, Siyao Wang, Richard Liu, Robert Barry, Stephen A Watts, John F Rawls, Michel Bagnat","doi":"10.7554/eLife.100611","DOIUrl":"10.7554/eLife.100611","url":null,"abstract":"Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome-rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene-assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to an increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623454","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

GATA6 regulates WNT and BMP programs to pattern precardiac mesoderm during the earliest stages of human cardiogenesis.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-13 DOI: 10.7554/eLife.100797

Joseph A Bisson, Miriam Gordillo, Ritu Kumar, Neranjan de Silva, Ellen Yang, Kelly M Banks, Zhong-Dong Shi, Kihyun Lee, Dapeng Yang, Wendy K Chung, Danwei Huangfu, Todd Evans

{"title":"GATA6 regulates WNT and BMP programs to pattern precardiac mesoderm during the earliest stages of human cardiogenesis.","authors":"Joseph A Bisson, Miriam Gordillo, Ritu Kumar, Neranjan de Silva, Ellen Yang, Kelly M Banks, Zhong-Dong Shi, Kihyun Lee, Dapeng Yang, Wendy K Chung, Danwei Huangfu, Todd Evans","doi":"10.7554/eLife.100797","DOIUrl":"10.7554/eLife.100797","url":null,"abstract":"Haploinsufficiency for GATA6 is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers, suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hr of cardiac differentiation is sufficient to partially rescue CPC and CM defects in GATA6 heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by human GATA6 mutations.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623915","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