CellPub Date : 2025-05-27DOI: 10.1016/j.cell.2025.05.003
Xiao-Qi Liu, Pan Li, Bao-Qing Gao, Heng-Le Zhu, Liang-Zhong Yang, Yang Wang, Yu-Yao Zhang, Hao Wu, Yu-Hang Pan, Lin Shan, Hongtao Yu, Li Yang, Ling-Ling Chen
{"title":"De novo assembly of nuclear stress bodies rearranges and enhances NFIL3 to restrain acute inflammatory responses","authors":"Xiao-Qi Liu, Pan Li, Bao-Qing Gao, Heng-Le Zhu, Liang-Zhong Yang, Yang Wang, Yu-Yao Zhang, Hao Wu, Yu-Hang Pan, Lin Shan, Hongtao Yu, Li Yang, Ling-Ling Chen","doi":"10.1016/j.cell.2025.05.003","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.003","url":null,"abstract":"The membrane-less nuclear stress bodies (nSBs), with <em>satellite III</em> (<em>SatIII</em>) RNAs as the hallmark, are present in primates upon sensing stresses. We report that <em>SatⅢ</em> DNAs, <em>SatⅢ</em> RNAs, and 30 nSB proteins assemble into well-organized structures shortly after stresses. The activated <em>SatⅢ</em> heterochromatin loci rapidly expand, resulting in reduced spatial distance and enhanced expression of adjacent genes, including the transcription suppressor <em>NFIL3</em>, which is known to dampen proinflammatory cytokine production. Rearranging <em>NFIL3</em> loci within the nSB territory enhances <em>NFIL3</em> chromatin accessibility and makes <em>NFIL3</em> promoters more accessible to transcription factors heat shock transcription factor 1 (HSF1) and bromodomain containing 4 (BRD4), which are also recruited to nSBs upon stresses. Human peripheral blood mononuclear cell (PBMC)-derived macrophages under heat shock plus pathogen-associated molecular pattern treatments exhibit increased <em>SatⅢ</em> and <em>NFIL3</em> expression, the latter of which suppresses key inflammatory cytokines. Importantly, <em>NFIL3</em> expression positively correlates with <em>SatⅢ</em> activation in septic patients, a process positively correlated to patient survival, highlighting a role of nSBs in restraining inflammatory responses.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"83 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-27DOI: 10.1016/j.cell.2025.05.001
Hosung Bae, Sunhee Jung, Johnny Le, Ian Tamburini, Joohwan Kim, Eric Wang, Won-Suk Song, Wonsuk Choi, Ki-Hong Jang, Taekyung Kang, Miranda L. Lopez, Cuauhtemoc Ramirez, Ipsita Mohanty, Miranda E. Kelly, Jessie Kim, Raymond Kim, Sang Hee Park, Jongwon Baek, Bryan Mendez, Paul Petrus, Cholsoon Jang
{"title":"Cross-organ metabolite production and consumption in healthy and atherogenic conditions","authors":"Hosung Bae, Sunhee Jung, Johnny Le, Ian Tamburini, Joohwan Kim, Eric Wang, Won-Suk Song, Wonsuk Choi, Ki-Hong Jang, Taekyung Kang, Miranda L. Lopez, Cuauhtemoc Ramirez, Ipsita Mohanty, Miranda E. Kelly, Jessie Kim, Raymond Kim, Sang Hee Park, Jongwon Baek, Bryan Mendez, Paul Petrus, Cholsoon Jang","doi":"10.1016/j.cell.2025.05.001","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.001","url":null,"abstract":"Mammalian organs continuously produce and consume circulating metabolites for organismal health and survival. However, the landscape of this fundamental process and its perturbation by diet and disease is unknown. Using arteriovenous metabolomics, tissue transcriptomics, and hormone arrays in multiple pathophysiological conditions in pigs, we generated an atlas of 10 cross-organ metabolite production and consumption during fasting/feeding, Western diet, and cardiovascular disease progression induced by low-density lipoprotein receptor (LDLR) deficiency. We discovered numerous instances of feeding-dependent and -independent metabolite production and consumption by organs and proposed mechanisms by which these are disrupted by Western diet via altered metabolite concentration gradients and hormones. Both Western diet and LDLR deficiency trigger the release of bile acids (BAs) by extra-hepatic organs, likely contributing to abnormally elevated circulating BA levels and consequent vascular inflammation and atherosclerosis development. These resources reveal intricate inter-organ metabolic crosstalk across pathophysiological conditions, offering biochemical insights into diet effects and cardiometabolic diseases.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"40 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-23DOI: 10.1016/j.cell.2025.05.004
Eva Breyer, Constanze Stix, Sophie Kilker, Benjamin R.K. Roller, Fragkiski Panagou, Charlotte Doebke, Chie Amano, Daniel E.M. Saavedra, Guillem Coll-García, Barbara Steger-Mähnert, Jordi Dachs, Naiara Berrojalbiz, Maria Vila-Costa, Cristina Sobrino, Antonio Fuentes-Lema, Franz Berthiller, Martin F. Polz, Federico Baltar
{"title":"The contribution of pelagic fungi to ocean biomass","authors":"Eva Breyer, Constanze Stix, Sophie Kilker, Benjamin R.K. Roller, Fragkiski Panagou, Charlotte Doebke, Chie Amano, Daniel E.M. Saavedra, Guillem Coll-García, Barbara Steger-Mähnert, Jordi Dachs, Naiara Berrojalbiz, Maria Vila-Costa, Cristina Sobrino, Antonio Fuentes-Lema, Franz Berthiller, Martin F. Polz, Federico Baltar","doi":"10.1016/j.cell.2025.05.004","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.004","url":null,"abstract":"Metagenomic analysis has recently unveiled the widespread presence of pelagic fungi in the global ocean, yet their quantitative contribution to carbon stocks remains elusive, hindering their incorporation into biogeochemical models. Here, we revealed the biomass of pelagic fungi in the open-ocean water column by combining ergosterol extraction, Calcofluor-White staining, catalyzed reporter deposition fluorescence <em>in situ</em> hybridization (CARD-FISH), and microfluidic mass sensor techniques. We compared fungal biomass with the biomass of other more studied microbial groups in the ocean such as archaea and bacteria. Globally, fungi contributed 0.32 Gt C (CI: 0.19–0.46), refining previous uncertainty estimates from two orders of magnitude to less than one. While fungal biomass was lower than that of bacteria, it exceeded that of the archaea (archaea:fungi:bacteria biomass ratio of 1:9:44). Collectively, our findings reveal the important contribution of fungi to open-ocean biomass and, consequently, the marine carbon cycle, emphasizing the need for their inclusion in biogeochemical models.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"44 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-23DOI: 10.1016/j.cell.2025.04.039
Xiao Yan, David Kuster, Priyesh Mohanty, Jik Nijssen, Karina Pombo-García, Jorge Garcia Morato, Azamat Rizuan, Titus M. Franzmann, Aleksandra Sergeeva, Anh M. Ly, Feilin Liu, Patricia M. Passos, Leah George, Szu-Huan Wang, Jayakrishna Shenoy, Helen L. Danielson, Busra Ozguney, Alf Honigmann, Yuna M. Ayala, Nicolas L. Fawzi, Anthony A. Hyman
{"title":"Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates","authors":"Xiao Yan, David Kuster, Priyesh Mohanty, Jik Nijssen, Karina Pombo-García, Jorge Garcia Morato, Azamat Rizuan, Titus M. Franzmann, Aleksandra Sergeeva, Anh M. Ly, Feilin Liu, Patricia M. Passos, Leah George, Szu-Huan Wang, Jayakrishna Shenoy, Helen L. Danielson, Busra Ozguney, Alf Honigmann, Yuna M. Ayala, Nicolas L. Fawzi, Anthony A. Hyman","doi":"10.1016/j.cell.2025.04.039","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.039","url":null,"abstract":"Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"137 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-22DOI: 10.1016/j.cell.2025.04.037
Jakob Trendel, Simon Trendel, Shuyao Sha, Franziska Greulich, Sandra Goll, Susanne I. Wudy, Karin Kleigrewe, Stefan Kubicek, N. Henriette Uhlenhaut, Bernhard Kuster
{"title":"The human proteome with direct physical access to DNA","authors":"Jakob Trendel, Simon Trendel, Shuyao Sha, Franziska Greulich, Sandra Goll, Susanne I. Wudy, Karin Kleigrewe, Stefan Kubicek, N. Henriette Uhlenhaut, Bernhard Kuster","doi":"10.1016/j.cell.2025.04.037","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.037","url":null,"abstract":"In a human cell, DNA is packed with histones, RNA, and chromatin-associated proteins, forming a cohesive gel. At any given moment, only a subset of the proteome has physical access to the DNA and organizes its structure, transcription, replication, repair, and other essential molecular functions. We have developed a “zero-distance” photo-crosslinking approach to quantify proteins in direct contact with DNA in living cells. Collecting DNA interactomes from human breast cancer cells, we present an atlas of over one thousand proteins with physical access to DNA and hundreds of peptide-nucleotide crosslinks pinpointing protein-DNA interfaces with single-amino-acid resolution. Quantitative comparisons of DNA interactomes from differentially treated cells recapitulate the recruitment of key transcription factors as well as DNA repair proteins and uncover fast-acting restrictors of chromatin accessibility on a timescale of minutes. This opens a direct way to explore genomic regulation in a hypothesis-free manner, applicable to many organisms and systems.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"3 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-22DOI: 10.1016/j.cell.2025.04.036
Xianwei Song, Shanjie Tang, Hui Liu, Ying Meng, Haofei Luo, Bao Wang, Xiu-Li Hou, Bin Yan, Chao Yang, Zhenhua Guo, Lizhi Wang, Shukun Jiang, Xian Deng, Xiaofeng Cao
{"title":"Inheritance of acquired adaptive cold tolerance in rice through DNA methylation","authors":"Xianwei Song, Shanjie Tang, Hui Liu, Ying Meng, Haofei Luo, Bao Wang, Xiu-Li Hou, Bin Yan, Chao Yang, Zhenhua Guo, Lizhi Wang, Shukun Jiang, Xian Deng, Xiaofeng Cao","doi":"10.1016/j.cell.2025.04.036","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.036","url":null,"abstract":"Epigenetic pathways could provide a mechanistic explanation for the inheritance of acquired characteristics, as proposed by Lamarck in 1802, but epigenetic alterations that endow adaptive hereditary traits have rarely been observed. Here, in cultivated Asian rice (<em>Oryza</em> <em>s</em><em>ativa</em> L.), we identified an epiallele conferring acquired and heritable cold tolerance, an adaptive trait enabling northward spread from its tropical origins. We subjected cold-sensitive rice to multigenerational cold stress and identified a line with acquired stable inheritance of cold tolerance. DNA-hypomethylation variation in the <em>a</em><em>cquired</em> <em>c</em><em>old</em> <em>t</em><em>olerance 1</em> (<em>ACT1</em>) promoter region rendered its expression insensitive to cold. This change is, in large part, responsible for the acquired cold tolerance, as confirmed by DNA-methylation editing. Natural variation in <em>ACT1</em> DNA hypomethylation is associated with cold tolerance and rice geographic distribution. Hypomethylation at <em>ACT1</em> triggers adaptive cold tolerance, presenting a route to epigenetic-variation-driven inheritance of acquired characteristics.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"44 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Near-infrared spatiotemporal color vision in humans enabled by upconversion contact lenses","authors":"Yuqian Ma, Yunuo Chen, Sheng Wang, Zi-Han Chen, Yuanwei Zhang, Ling Huang, Xinxin Zhang, Fei Yin, Yunxuan Wang, Mingzhu Yang, Zhanjun Li, Kai Huang, Xin Fang, Zishuo Li, Minghong Wang, Wenhui Liu, Jia-Nan Li, Longfei Li, Hang Zhao, Min Wei, Tian Xue","doi":"10.1016/j.cell.2025.04.019","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.019","url":null,"abstract":"Humans cannot perceive infrared light due to the physical thermodynamic properties of photon-detecting opsins. However, the capability to detect invisible multispectral infrared light with the naked eye is highly desirable. Here, we report wearable near-infrared (NIR) upconversion contact lenses (UCLs) with suitable optical properties, hydrophilicity, flexibility, and biocompatibility. Mice with UCLs could recognize NIR temporal and spatial information and make behavioral decisions. Furthermore, human participants wearing UCLs could discriminate NIR information, including temporal coding and spatial images. Notably, we have developed trichromatic UCLs (tUCLs), allowing humans to distinguish multiple spectra of NIR light, which can function as three primary colors, thereby achieving human NIR spatiotemporal color vision. Our research opens up the potential of wearable polymeric materials for non-invasive NIR vision, assisting humans in perceiving and transmitting temporal, spatial, and color dimensions of NIR light.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-21DOI: 10.1016/j.cell.2025.05.002
Yoav Ben-Simon, Marcus Hooper, Sujatha Narayan, Tanya L. Daigle, Deepanjali Dwivedi, Sharon W. Way, Aaron Oster, David A. Stafford, John K. Mich, Michael J. Taormina, Refugio A. Martinez, Ximena Opitz-Araya, Jada R. Roth, Jason R. Alexander, Shona Allen, Adam Amster, Joel Arbuckle, Angela Ayala, Pamela M. Baker, Trygve E. Bakken, Bosiljka Tasic
{"title":"A suite of enhancer AAVs and transgenic mouse lines for genetic access to cortical cell types","authors":"Yoav Ben-Simon, Marcus Hooper, Sujatha Narayan, Tanya L. Daigle, Deepanjali Dwivedi, Sharon W. Way, Aaron Oster, David A. Stafford, John K. Mich, Michael J. Taormina, Refugio A. Martinez, Ximena Opitz-Araya, Jada R. Roth, Jason R. Alexander, Shona Allen, Adam Amster, Joel Arbuckle, Angela Ayala, Pamela M. Baker, Trygve E. Bakken, Bosiljka Tasic","doi":"10.1016/j.cell.2025.05.002","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.002","url":null,"abstract":"The mammalian cortex is comprised of cells classified into types according to shared properties. Defining the contribution of each cell type to the processes guided by the cortex is essential for understanding its function in health and disease. We use transcriptomic and epigenomic cortical cell-type taxonomies from mouse and human to define marker genes and putative enhancers and create a large toolkit of transgenic lines and enhancer adeno-associated viruses (AAVs) for selective targeting of cortical cell populations. We report creation and evaluation of fifteen transgenic driver lines, two reporter lines, and >1,000 different enhancer AAV vectors covering most subclasses of cortical cells. The tools reported here have been made publicly available, and along with the scaled process of tool creation, evaluation, and modification, they will enable diverse experimental strategies toward understanding mammalian cortex and brain function.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"131 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2025-05-21DOI: 10.1016/j.cell.2025.04.032
Bo Li, James Elsten-Brown, Miao Li, Enbo Zhu, Zhe Li, Yuning Chen, Elliot Kang, Feiyang Ma, Jennifer Chiang, Yan-Ruide Li, Yichen Zhu, Jie Huang, Audrey Fung, Quentin Scarborough, Robin Cadd, Jin J. Zhou, Arnold I. Chin, Matteo Pellegrini, Lili Yang
{"title":"Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis","authors":"Bo Li, James Elsten-Brown, Miao Li, Enbo Zhu, Zhe Li, Yuning Chen, Elliot Kang, Feiyang Ma, Jennifer Chiang, Yan-Ruide Li, Yichen Zhu, Jie Huang, Audrey Fung, Quentin Scarborough, Robin Cadd, Jin J. Zhou, Arnold I. Chin, Matteo Pellegrini, Lili Yang","doi":"10.1016/j.cell.2025.04.032","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.032","url":null,"abstract":"Identifying additional immune checkpoints hindering antitumor T cell responses is key to the development of next-generation cancer immunotherapies. Here, we report the induction of serotonin transporter (SERT), a regulator of serotonin levels and physiological functions in the brain and peripheral tissues, in tumor-infiltrating CD8 T cells. Inhibition of SERT using selective serotonin reuptake inhibitors (SSRIs), the most widely prescribed antidepressants, significantly suppressed tumor growth and enhanced T cell antitumor immunity in various mouse syngeneic and human xenograft tumor models. Importantly, SSRI treatment exhibited significant therapeutic synergy with programmed cell death protein 1 (PD-1) blockade, and clinical data correlation studies negatively associated intratumoral <em>SERT</em> expression with patient survival in a range of cancers. Mechanistically, SERT functions as a negative-feedback regulator inhibiting CD8 T cell reactivities by depleting intratumoral T cell-autocrine serotonin. These findings highlight the significance of the intratumoral serotonin axis and identify SERT as an immune checkpoint, positioning SSRIs as promising candidates for cancer immunotherapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"70 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Integrating reproductive states and social cues in the control of sociosexual behaviors","authors":"Yuping Wang, Xinli Song, Xiangmao Chen, Ying Zhou, Jihao Ma, Fang Zhang, Liqiang Wei, Guoxu Qi, Nakul Yadav, Benjie Miao, Yiming Yan, Guohua Yuan, Da Mi, Priyamvada Rajasethupathy, Ines Ibañez-Tallon, Xiaoxuan Jia, Nathaniel Heintz, Kun Li","doi":"10.1016/j.cell.2025.04.035","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.035","url":null,"abstract":"Female sociosexual behaviors, essential for survival and reproduction, are modulated by ovarian hormones and triggered in the context of appropriate social cues. Here, we identify primary estrous-sensitive Cacna1h-expressing medial prefrontal cortex (mPFC<sup>Cacna1h+</sup>) neurons that integrate hormonal states with recognition of potential mates to orchestrate these complex cognitive behaviors. Bidirectional manipulation of mPFC<sup>Cacna1h+</sup> neurons shifts opposite-sex-directed social behaviors between estrus and diestrus females via anterior hypothalamic outputs. In males, these neurons serve opposite functions compared with estrus females. Miniscope imaging reveals mixed representation of self-estrous states and social target sex in distinct mPFC<sup>Cacna1h+</sup> subpopulations, with biased encoding of opposite-sex cues in estrus females and males. Mechanistically, ovarian-hormone-induced Cacna1h upregulation enhances T-type rebound excitation after oxytocin inhibition, driving estrus-specific activity changes and the sexually dimorphic function of mPFC<sup>Cacna1h+</sup> neurons. These findings uncover a prefrontal circuit that integrates internal hormonal states and target-sex information to exert sexually bivalent top-down control over adaptive social behaviors.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"97 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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