EMBO JournalPub Date : 2025-10-01Epub Date: 2025-08-18DOI: 10.1038/s44318-025-00528-8
Dongteng Liu, Yuxiang Zhang, Dongliang Li, Binjie Jiang, Xudong Zhao, Yanyan Li, Zexiong Lin, Yu Zhao, Zhe Hu, Shuzi Deng, Zheng Li, Haonan Lu, Karen K L Chan, William S B Yeung, Philipp Kaldis, Chencheng Yao, Hengbin Wang, Louise T Chow, Kui Liu
{"title":"Speedy A governs non-homologous XY chromosome desynapsis as a unique prerequisite for XY loop-axis organization.","authors":"Dongteng Liu, Yuxiang Zhang, Dongliang Li, Binjie Jiang, Xudong Zhao, Yanyan Li, Zexiong Lin, Yu Zhao, Zhe Hu, Shuzi Deng, Zheng Li, Haonan Lu, Karen K L Chan, William S B Yeung, Philipp Kaldis, Chencheng Yao, Hengbin Wang, Louise T Chow, Kui Liu","doi":"10.1038/s44318-025-00528-8","DOIUrl":"10.1038/s44318-025-00528-8","url":null,"abstract":"<p><p>In mouse early pachytene spermatocytes, the X and Y chromosomes undergo rapid non-homologous (NH) synapsis and desynapsis, but the functional significance remains unknown. Here, we report that pachynema-specific knockout of Speedy A (SpdyA) from telomeres caused persistent Y-X NH synapsis, with the entire Y axis synapsed onto the X axis. This persistent Y-X NH synapsis did not interrupt meiotic sex chromosome inactivation, recombination, or sex body formation, but it disrupted X-Y loop-axis organization and homologous X-Y desynapsis, leading to spermatocyte death. Similarly, persistent Y-X NH synapsis was also observed in pachytene spermatocytes lacking TRF1, where SpdyA was frequently lost from the X-Y non-pseudoautosomal region (non-PAR) telomeres. Mechanistic studies revealed that Serine 48 of SUN1 is a key SpdyA/CDK2 phosphorylation site required for Y-X NH desynapsis. We propose that SpdyA governs Y-X NH desynapsis by stabilizing the linkage between the X-Y non-PAR telomeres and their LINC complexes, and that this process is regulated independently from other aspects of pachynema progression. Our findings suggest a key role for Y-X NH desynapsis in establishing proper X-Y loop-axis organization.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5509-5536"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876544","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-08-22DOI: 10.1038/s44318-025-00542-w
Jessica Karta, Marianne Meyers, Fabien Rodriguez, Eric Koncina, Cedric Gilson, Eliane Klein, Monica Gabola, Mohaned Benzarti, Pau Pérez Escriva, Jose Alberto Molina Tijeras, Catarina Correia Tavares Bernardino, Falk Ponath, Anais Carpentier, Mònica Aguilera Pujabet, Maryse Schmoetten, Mina Tsenkova, Perla Saoud, Anthoula Gaigneaux, Dominik Ternes, Lidia Alonso, Nikolaus Zügel, Eric Willemssen, Philippe Koppes, Daniel Léonard, Luis Perez Casanova, Serge Haan, Michel Mittelbronn, Johannes Meiser, Vitaly I Pozdeev, Jörg Vogel, Paolo G Nuciforo, Paul Wilmes, Elisabeth Letellier
{"title":"Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer.","authors":"Jessica Karta, Marianne Meyers, Fabien Rodriguez, Eric Koncina, Cedric Gilson, Eliane Klein, Monica Gabola, Mohaned Benzarti, Pau Pérez Escriva, Jose Alberto Molina Tijeras, Catarina Correia Tavares Bernardino, Falk Ponath, Anais Carpentier, Mònica Aguilera Pujabet, Maryse Schmoetten, Mina Tsenkova, Perla Saoud, Anthoula Gaigneaux, Dominik Ternes, Lidia Alonso, Nikolaus Zügel, Eric Willemssen, Philippe Koppes, Daniel Léonard, Luis Perez Casanova, Serge Haan, Michel Mittelbronn, Johannes Meiser, Vitaly I Pozdeev, Jörg Vogel, Paolo G Nuciforo, Paul Wilmes, Elisabeth Letellier","doi":"10.1038/s44318-025-00542-w","DOIUrl":"10.1038/s44318-025-00542-w","url":null,"abstract":"<p><p>Gut microbial species contribute to colorectal cancer (CRC) by interacting with tumor or immune cells, however if CRC-associated bacteria engage with stromal components of the tumor microenvironment remains unclear. Here, we report interaction between the CRC-associated bacterium Fusobacterium nucleatum and cancer-associated fibroblasts (CAFs), and show that F. nucleatum is present in the stromal compartment in murine CRC models in vivo and can attach to and invade CAFs. F. nucleatum-exposed CAFs exhibit a pronounced inflammatory-CAF (iCAF) phenotype, marked by elevated expression of established iCAF markers, secretion of pro-inflammatory cytokines such as CXCL1, IL-6 and IL-8, generation of reactive oxygen species (ROS), and an increased metabolic activity. In co-culture experiments, the interaction of cancer cells with F. nucleatum-stimulated CAFs enhances invasion, a finding further validated in vivo. Altogether, our results point to a role for the tumor microbiome in CRC progression by remodeling the tumor microenvironment through its influence on cancer-associated fibroblasts, suggesting novel therapeutic strategies for targeting CRC.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5375-5393"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977206","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-09-01DOI: 10.1038/s44318-025-00539-5
Yagmur Keser, Camila Metz-Zumaran, Zina M Uckeley, Dorothee Reuss, Patricio Doldan, James M Ramsden, Megan L Stanifer, Steeve Boulant
{"title":"Basal IFN-λ2/3 expression mediates tight junction formation in human epithelial cells.","authors":"Yagmur Keser, Camila Metz-Zumaran, Zina M Uckeley, Dorothee Reuss, Patricio Doldan, James M Ramsden, Megan L Stanifer, Steeve Boulant","doi":"10.1038/s44318-025-00539-5","DOIUrl":"10.1038/s44318-025-00539-5","url":null,"abstract":"<p><p>Type-III interferons (or IFNλs) play important roles in antiviral defense and intestinal epithelial barrier integrity. While interferon expression has been primarily studied in response to pathogens, basal interferon expression also occurs in pathogen-free environments. However, the mechanisms regulating basal IFN-λ expression and their functions have not yet been elucidated. Here, we show that basal IFN-λ2/3 expression is linked to the development of an intact cellular epithelium characterized by formation of tight junctions and establishment of barrier function. Our findings indicate that basal IFN-λ2/3 expression depends on cGAS-STING-mediated mitochondrial DNA detection, while it is inhibited by the Hippo mechanotransduction pathway at low cellular densities. Cells lacking basal IFN-λ2/3 expression fail to develop proper tight junctions and establish normal barrier function. Mechanistically, IFN-λ2/3 suppresses Claudin-2 expression, thereby promoting barrier formation as cells become confluent. These results demonstrate a previously unknown function of basal IFNλ expression in regulating epithelial cell junction formation and highlight their importance not only during pathogen challenges but also in maintaining epithelial cell function under steady-state conditions.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5785-5815"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977176","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-09-03DOI: 10.1038/s44318-025-00534-w
Matylda Zietek, Amanda Miguel, Handuo Shi, Iskander Khusainov, Abir T Asmar, Sri Ram, Morgane Wartel, Anna Sueki, Martin Schorb, Mark Goulian, Jean-François Collet, Martin Beck, Kerwyn Casey Huang, Athanasios Typas
{"title":"Bacterial cell widening alters periplasmic size and activates envelope stress responses.","authors":"Matylda Zietek, Amanda Miguel, Handuo Shi, Iskander Khusainov, Abir T Asmar, Sri Ram, Morgane Wartel, Anna Sueki, Martin Schorb, Mark Goulian, Jean-François Collet, Martin Beck, Kerwyn Casey Huang, Athanasios Typas","doi":"10.1038/s44318-025-00534-w","DOIUrl":"10.1038/s44318-025-00534-w","url":null,"abstract":"<p><p>The Rcs signal transduction system is a phosphorelay responsible for sensing enterobacterial cell envelope stresses. In Escherichia coli, the Rcs system is required to survive treatment with A22 and mecillinam, antibiotics that perturb cell size. To test whether size changes are correlated with envelope damage and thereby sensed by the Rcs system, we tuned E. coli cell size via A22 treatment, mutations in the cell-shape determinant MreB, and mechanically confined growth. In all conditions, cell width was strongly correlated with Rcs activation, and RcsF, the outer-membrane-localized upstream component, was essential for responding to cell width changes. Several gene deletions that induce Rcs resulted in cells that were wider than wild-type. Cryo-electron microscopy revealed that the periplasm of a wide MreB mutant is ~3 nm thinner than in wild-type cells, bringing RcsF closer to the downstream, inner-membrane-localized components of the signaling cascade. Conversely, extending the RcsF linker region in wild-type cells by ~3 nm increased Rcs activity. Thus, we propose that the Rcs system responds to changes in cell width due to altered periplasmic thickness.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5816-5833"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994352","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-09-09DOI: 10.1038/s44318-025-00555-5
Stewart W C Masson, Rebecca C Simpson, Harry B Cutler, Patrick W Carlos, Oana C Marian, Belinda Yau, Meg Potter, Søren Madsen, Kristen C Cooke, Niamh R Craw, Oliver K Fuller, Dylan J Harney, Mark Larance, Gregory J Cooney, Grant Morahan, Erin R Shanahan, Melkam A Kebede, Christopher Hodgkins, Richard J Payne, Jacqueline Stöckli, David E James
{"title":"Genetic variance in the murine defensin locus modulates glucose homeostasis.","authors":"Stewart W C Masson, Rebecca C Simpson, Harry B Cutler, Patrick W Carlos, Oana C Marian, Belinda Yau, Meg Potter, Søren Madsen, Kristen C Cooke, Niamh R Craw, Oliver K Fuller, Dylan J Harney, Mark Larance, Gregory J Cooney, Grant Morahan, Erin R Shanahan, Melkam A Kebede, Christopher Hodgkins, Richard J Payne, Jacqueline Stöckli, David E James","doi":"10.1038/s44318-025-00555-5","DOIUrl":"10.1038/s44318-025-00555-5","url":null,"abstract":"<p><p>Insulin resistance is a heritable risk factor for many chronic diseases; however, the genetic drivers remain elusive. In seeking these, we performed genetic mapping of insulin sensitivity in 670 chow-fed Diversity Outbred in Australia (DOz) mice and identified a genome-wide significant locus (QTL) on chromosome 8 encompassing 17 defensin genes. By taking a systems genetics approach, we identified alpha-defensin 26 (Defa26) as the causal gene in this region. To validate these findings, we synthesized Defa26 and performed diet supplementation experiments in two mouse strains with distinct endogenous Defa26 expression levels. In the strain with relatively lower endogenous expression (C57BL/6J) supplementation improved insulin sensitivity and reduced gut permeability, while in the strain with higher endogenous expression (A/J) it caused hypoinsulinemia, glucose intolerance and muscle wasting. Based on gut microbiome and plasma bile acid profiling this appeared to be the result of disrupted microbial bile acid metabolism. These data illustrate the danger of single strain over-reliance and provide the first evidence of a link between host-genetics and insulin sensitivity which is mediated by the microbiome.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5694-5711"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031190","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-08-26DOI: 10.1038/s44318-025-00519-9
Gokcen Gozum, Lakshit Sharma, Paula Henke, Lisa Wirtz, Mareike Damen, Viktoria Reckert, Peter Schettina, Melanie Nelles, Craig N Johnson, Hisham Bazzi, Catherin Niemann
{"title":"Specific and redundant roles for Gli2 and Gli3 in establishing cell fate during murine hair follicle development.","authors":"Gokcen Gozum, Lakshit Sharma, Paula Henke, Lisa Wirtz, Mareike Damen, Viktoria Reckert, Peter Schettina, Melanie Nelles, Craig N Johnson, Hisham Bazzi, Catherin Niemann","doi":"10.1038/s44318-025-00519-9","DOIUrl":"10.1038/s44318-025-00519-9","url":null,"abstract":"<p><p>Formation of skin epithelial appendages like hair follicles requires hedgehog (Hh) signal reception, its conduction through the primary cilium and activation of Gli transcription factors. How Hh signalling induces cell-type-specific responses through Gli transcription factors in hair follicle stem cells and their cilia-dependence remains unclear. Here, we use conditional mouse mutants to genetically dissect the roles of Gli2 and Gli3 transcription factors and cilia in the skin epithelium. Upon keratinocyte-specific depletion of Gli2, hair follicle morphogenesis is delayed whereas sebaceous gland formation is enhanced, suggesting a dual role for Gli2 during appendage development. Gli2 promotes proliferation of sebaceous gland stem cells, impacting the number and size of individual sebaceous gland lobes. While ablation of Gli3 shows no detectable phenotypes, hair follicle cell fate is blocked in Gli2/Gli3 double knockout (dKO) mice, suggesting functional compensation. Finally, loss of cilia phenocopies the depletion of Gli2 but not the Gli2/3 dKO mutants. Our study reveals compartment-specific regulation of murine skin morpohogenesis by Gli2 and cilia-independent activator functions of Gli3 in the absence of Gli2.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5290-5314"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977290","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-08-29DOI: 10.1038/s44318-025-00531-z
Zhixun Dou, Jill A Kreiling, Susanne Heynen-Genel, Diana Jurk, Nicola Neretti, Peter D Adams, John M Sedivy, João F Passos
{"title":"Cytosolic DNA crosstalk in senescence: a new axis of inflammatory signaling?","authors":"Zhixun Dou, Jill A Kreiling, Susanne Heynen-Genel, Diana Jurk, Nicola Neretti, Peter D Adams, John M Sedivy, João F Passos","doi":"10.1038/s44318-025-00531-z","DOIUrl":"10.1038/s44318-025-00531-z","url":null,"abstract":"","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5239-5243"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977225","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-09-01DOI: 10.1038/s44318-025-00553-7
Lijun Chen, Chao Peng, Lanyi Chai, Renjie Zhang, Chenghang Zhu, Hailin Wang, Qirong Cheng, Yan Yan, Cailiang Shen, Hong Zheng, Jiazhao Yang, Haitao Fan, Chen Kan
{"title":"GNAS/PKA signaling promotes aberrant osteochondral differentiation of Gli1<sup>+</sup> tendon sheath progenitors.","authors":"Lijun Chen, Chao Peng, Lanyi Chai, Renjie Zhang, Chenghang Zhu, Hailin Wang, Qirong Cheng, Yan Yan, Cailiang Shen, Hong Zheng, Jiazhao Yang, Haitao Fan, Chen Kan","doi":"10.1038/s44318-025-00553-7","DOIUrl":"10.1038/s44318-025-00553-7","url":null,"abstract":"<p><p>Tendon injury promotes aberrant osteochondral differentiation of tendon stem cells (TSCs) and results in disability. However, the cellular subsets within the osteochondral lineage involved in this process and associated mechanisms remain unclear. Here, we found that, following Achilles tenotomy, murine Gli1<sup>+</sup> tendon sheath cells expanded rapidly, transitioning into tenogenic and osteochondrogenic cells. Lineage tracing, together with single-cell RNA sequencing, revealed that osteochondrogenic Gli1<sup>+</sup> tendon sheath cells originate from Scx<sup>+</sup> tendon stem/progenitor cells, preferentially differentiate into osteochondral lineage tendon progenitors at 7 dpi, subsequently undergoing aberrant chondrogenesis and osteogenesis at 21dpi and 63dpi, respectively. In addition, Acvr1<sup>R206H/+</sup> robustly accelerates osteochondral differentiation in Gli1<sup>+</sup> tendon sheath progenitors. Furthermore, GNAS/PKA signaling was significantly activated in osteochondral differentiation of Gli1<sup>+</sup> tendon sheath progenitors. Alternatively, treatment with the G<sub>sα</sub> antagonist, NF449, or genetic inhibition of the PKA subunit, Prkaca, in Gli1<sup>+</sup> sheath progenitors significantly alleviated aberrant osteochondral differentiation. NF449 also prevented osteochondral differentiation of human tendon stem cells. These findings identify Gli1<sup>+</sup> tendon sheath progenitors with osteochondral differentiation capacity during heterotopic ossification via activation of GNAS/PKA signaling, suggesting PKA as a potentially effective therapeutic target to treat tendon ossification.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5890-5917"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977209","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-08-26DOI: 10.1038/s44318-025-00537-7
Irene Salas-Armenteros, Maarten Klunder, Wim Vermeulen, Maria Tresini
{"title":"Crosstalk between chromatin state and ATM signalling in DNA damage-induced transcription stress.","authors":"Irene Salas-Armenteros, Maarten Klunder, Wim Vermeulen, Maria Tresini","doi":"10.1038/s44318-025-00537-7","DOIUrl":"10.1038/s44318-025-00537-7","url":null,"abstract":"<p><p>The DNA Damage Response (DDR) is a highly regulated process that safeguards genomic integrity against DNA lesions. Increasing evidence supports a reciprocal relationship between damaged chromatin architecture and the signalling pathways that coordinate the DDR. However, the mechanisms underlying this interplay in response to transcription-blocking DNA lesions remain largely unexplored. Here, we show that stalling of RNA polymerase II (RNAPII) at such lesions induces local chromatin acetylation, mediated primarily by the histone acetyltransferase p300. The resulting chromatin relaxation stimulates the dissociation of mature co-transcriptional spliceosomes from nascent RNA and promotes RNA:DNA hybrid (R-loop) formation, leading to ATM activation. In turn, activated ATM modulates chromatin conformation by phosphorylating histone H2A.X and triggering p38MAPK/MSK1-dependent histone H3S10 phosphorylation. Our findings highlight the cross-regulation between chromatin state and ATM signalling as a key component of the cellular response to transcription stress.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5564-5594"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977203","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}
EMBO JournalPub Date : 2025-10-01Epub Date: 2025-08-20DOI: 10.1038/s44318-025-00524-y
Katharina Sieckmann, Nora Winnerling, Dalila Juliana Silva Ribeiro, Seniz Yüksel, Ronja Kardinal, Lisa Maria Steinheuer, Fabian Frechen, Luis Henrique Corrêa, Geza Schermann, Christina Klausen, Nelli Blank-Stein, Jonas Schulte-Schrepping, Collins Osei-Sarpong, Matthias Becker, Lorenzo Bonaguro, Marc Beyer, Helen Louise May-Simera, Jelena Zurkovic, Christoph Thiele, Kevin Thurley, Lydia Sorokin, Carmen Ruiz de Almodovar, Elvira Mass, Dagmar Wachten
{"title":"BBS8-dependent ciliary Hedgehog signaling governs cell fate in the white adipose tissue.","authors":"Katharina Sieckmann, Nora Winnerling, Dalila Juliana Silva Ribeiro, Seniz Yüksel, Ronja Kardinal, Lisa Maria Steinheuer, Fabian Frechen, Luis Henrique Corrêa, Geza Schermann, Christina Klausen, Nelli Blank-Stein, Jonas Schulte-Schrepping, Collins Osei-Sarpong, Matthias Becker, Lorenzo Bonaguro, Marc Beyer, Helen Louise May-Simera, Jelena Zurkovic, Christoph Thiele, Kevin Thurley, Lydia Sorokin, Carmen Ruiz de Almodovar, Elvira Mass, Dagmar Wachten","doi":"10.1038/s44318-025-00524-y","DOIUrl":"10.1038/s44318-025-00524-y","url":null,"abstract":"<p><p>The primary cilium plays a crucial role in regulating whole-body energy metabolism, as reflected in Bardet-Biedl syndrome (BBS), where ciliary dysfunction leads to obesity due to hyperphagia and white adipose tissue (WAT) remodeling. Regulation of the fate and differentiation of adipocyte precursor cells (APCs) is essential for maintaining WAT homeostasis during obesity. Using Bbs8<sup>-/-</sup> mice that recapitulate the BBS patient phenotype, we demonstrate that primary cilia dysfunction reduces the stem-cell-like P1 APC subpopulation by inducing a phenotypic switch to a fibrogenic progenitor state. This switch is characterized by extracellular matrix (ECM) remodeling and upregulation of the fibrosis marker CD9, even before the onset of obesity. Single-cell RNA sequencing reveals a direct transition of P1 APCs into fibrogenic progenitors, bypassing the committed P2 progenitor state. Ectopic ciliary Hedgehog signaling upon loss of BBS8 appears as a central driver of the molecular changes in Bbs8<sup>-/-</sup> APCs, altering their differentiation into adipocytes and promoting their lipid uptake. These findings unravel a novel role for primary cilia in governing APC fate by determining the balance between adipogenesis and fibrogenesis, and suggest potential therapeutic targets for obesity.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5315-5336"},"PeriodicalIF":8.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977165","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}
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