EMBO Journal最新文献_第10页

A versatile toolbox for determining IRES activity in cells and embryonic tissues. 用于测定细胞和胚胎组织中IRES活性的多功能工具箱。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-05-01 Epub Date: 2025-03-13 DOI: 10.1038/s44318-025-00404-5

Philipp Koch, Zijian Zhang, Naomi R Genuth, Teodorus Theo Susanto, Martin Haimann, Alena Khmelinskaia, Gun Woo Byeon, Saurabh Dey, Maria Barna, Kathrin Leppek

{"title":"A versatile toolbox for determining IRES activity in cells and embryonic tissues.","authors":"Philipp Koch, Zijian Zhang, Naomi R Genuth, Teodorus Theo Susanto, Martin Haimann, Alena Khmelinskaia, Gun Woo Byeon, Saurabh Dey, Maria Barna, Kathrin Leppek","doi":"10.1038/s44318-025-00404-5","DOIUrl":"10.1038/s44318-025-00404-5","url":null,"abstract":"Widespread control of gene expression through translation has emerged as a key level of spatiotemporal regulation of protein expression. A prominent mechanism by which ribosomes can confer gene regulation is via internal ribosomal entry sites (IRESes), whose functions have however, remained difficult to rigorously characterize. Here we present a set of technologies in embryos and cells, including IRES-mediated translation of circular RNA (circRNA) reporters, single-molecule messenger (m)RNA isoform imaging, PacBio long-read sequencing, and isoform-sensitive mRNA quantification along polysome profiles as a new toolbox for understanding IRES regulation. Using these techniques, we investigate a broad range of cellular IRES RNA elements including Hox IRESes. We show IRES-dependent translation in circRNAs, as well as the relative expression, localization, and translation of an IRES-containing mRNA isoform in specific embryonic tissues. We thereby provide a new resource of technologies to elucidate the roles of versatile IRES elements in gene regulation and embryonic development.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2695-2724"},"PeriodicalIF":9.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626659","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

HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells. HAND1水平控制着来自人类多能干细胞的多能心脏和胚胎外祖细胞的分化。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-05-01 Epub Date: 2025-03-31 DOI: 10.1038/s44318-025-00409-0

Adam T Lynch, Naomi Phillips, Megan Douglas, Marta Dorgnach, I-Hsuan Lin, Antony D Adamson, Zoulfia Darieva, Jessica Whittle, Neil A Hanley, Nicoletta Bobola, Matthew J Birket

{"title":"HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells.","authors":"Adam T Lynch, Naomi Phillips, Megan Douglas, Marta Dorgnach, I-Hsuan Lin, Antony D Adamson, Zoulfia Darieva, Jessica Whittle, Neil A Hanley, Nicoletta Bobola, Matthew J Birket","doi":"10.1038/s44318-025-00409-0","DOIUrl":"10.1038/s44318-025-00409-0","url":null,"abstract":"Diverse sets of progenitors contribute to the development of the embryonic heart, but the mechanisms of their specification have remained elusive. Here, using a human pluripotent stem cell (hPSC) model, we deciphered cardiac and non-cardiac lineage trajectories in differentiation and identified transcription factors underpinning cell specification, identity and function. We discovered a concentration-dependent, fate determining function for the basic helix-loop-helix transcription factor HAND1 in mesodermal progenitors and uncovered its gene regulatory network. At low expression level, HAND1 directs differentiation towards multipotent juxta-cardiac field progenitors able to make cardiomyocytes and epicardial cells, whereas at high level it promotes the development of extraembryonic mesoderm. Importantly, HAND1-low progenitors can be propagated in their multipotent state. This detailed mechanistic insight into human development has the potential to accelerate the delivery of effective disease modelling, including for congenital heart disease, and cell therapy-based regenerative medicine.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2541-2565"},"PeriodicalIF":9.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755634","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

Recurrent innovation of protein-protein interactions in the Drosophila piRNA pathway. 果蝇piRNA通路中蛋白质相互作用的反复创新。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-24 DOI: 10.1038/s44318-025-00439-8

Sebastian Riedelbauch, Sarah Masser, Sandra Fasching, Sung-Ya Lin, Harpreet Kaur Salgania, Mie Aarup, Anja Ebert, Mandy Jeske, Mia T Levine, Ulrich Stelzl, Peter Andersen

{"title":"Recurrent innovation of protein-protein interactions in the Drosophila piRNA pathway.","authors":"Sebastian Riedelbauch, Sarah Masser, Sandra Fasching, Sung-Ya Lin, Harpreet Kaur Salgania, Mie Aarup, Anja Ebert, Mandy Jeske, Mia T Levine, Ulrich Stelzl, Peter Andersen","doi":"10.1038/s44318-025-00439-8","DOIUrl":"10.1038/s44318-025-00439-8","url":null,"abstract":"Despite being essential for fertility, genome-defense-pathway genes often evolve rapidly. However, little is known about the molecular basis of this adaptation. Here, we characterized the evolution of a protein interaction network within the PIWI-interacting small RNA (piRNA) genome-defense pathway in Drosophila at unprecedented scale and evolutionary resolution. We uncovered the pervasive rapid evolution of a protein interaction network anchored at the heterochromatin protein 1 (HP1) paralog Rhino. Through cross-species high-throughput yeast-two-hybrid screening, we identified three distinct evolutionary protein interaction trajectories across ~40 million years of Drosophila evolution. While several protein interactions are fully conserved, indicating functional conservation despite rapid amino acid-sequence change, other interactions are preserved through coevolution and were detected only between proteins within or from closely related species. We also identified species-restricted protein interactions, revealing insight into the mechanistic diversity and ongoing molecular innovation in Drosophila piRNA production. In sum, our analyses reveal principles of interaction evolution in an adaptively evolving protein-protein interaction network, and support intermolecular interaction innovation as a central molecular mechanism of evolutionary adaptation in protein-coding genes.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056256","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}

引用次数: 0

Drosophila Alms1 proteins regulate centriolar cartwheel assembly by enabling Plk4-Ana2 amplification loop. 果蝇 Alms1 蛋白通过启用 Plk4-Ana2 扩增环路来调控中心极车轮组装。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-28 DOI: 10.1038/s44318-025-00382-8

Marine Brunet, Joëlle Thomas, Jean-André Lapart, Léo Krüttli, Marine H Laporte, Maria Giovanna Riparbelli, Giuliano Callaini, Bénédicte Durand, Véronique Morel

{"title":"Drosophila Alms1 proteins regulate centriolar cartwheel assembly by enabling Plk4-Ana2 amplification loop.","authors":"Marine Brunet, Joëlle Thomas, Jean-André Lapart, Léo Krüttli, Marine H Laporte, Maria Giovanna Riparbelli, Giuliano Callaini, Bénédicte Durand, Véronique Morel","doi":"10.1038/s44318-025-00382-8","DOIUrl":"10.1038/s44318-025-00382-8","url":null,"abstract":"Centrioles play a central role in cell division by recruiting pericentriolar material (PCM) to form the centrosome. Alterations in centriole number or function lead to various diseases including cancer or microcephaly. Centriole duplication is a highly conserved mechanism in eukaryotes. Here, we show that the two Drosophila orthologs of the Alström syndrome protein 1 (Alms1a and Alms1b) are unexpected novel players of centriole duplication in fly. Using Ultrastructure Expansion Microscopy, we reveal that Alms1a is a PCM protein that is loaded proximally on centrioles at the onset of procentriole formation, whereas Alms1b caps the base of mature centrioles. We demonstrate that chronic loss of Alms1 proteins (with RNA null alleles) affects PCM maturation, whereas their acute loss (in RNAi KD) completely disrupts procentriole formation before Sas-6 cartwheel assembly. We establish that Alms1 proteins are required for the amplification of the Plk4-Ana2 pool at the duplication site and the subsequent Sas-6 recruitment. Thus, Alms1 proteins are novel critical but highly buffered regulators of PCM and cartwheel assembly in flies.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2366-2395"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532030","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

The MAST kinase KIN-4 carries out mitotic entry functions of Greatwall in C. elegans. MAST激酶KIN-4在秀丽隐杆线虫中执行Greatwall的有丝分裂进入功能。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-17 DOI: 10.1038/s44318-025-00364-w

Ludivine Roumbo, Batool Ossareh-Nazari, Suzanne Vigneron, Ioanna Stefani, Lucie Van Hove, Véronique Legros, Guillaume Chevreux, Benjamin Lacroix, Anna Castro, Nicolas Joly, Thierry Lorca, Lionel Pintard

{"title":"The MAST kinase KIN-4 carries out mitotic entry functions of Greatwall in C. elegans.","authors":"Ludivine Roumbo, Batool Ossareh-Nazari, Suzanne Vigneron, Ioanna Stefani, Lucie Van Hove, Véronique Legros, Guillaume Chevreux, Benjamin Lacroix, Anna Castro, Nicolas Joly, Thierry Lorca, Lionel Pintard","doi":"10.1038/s44318-025-00364-w","DOIUrl":"10.1038/s44318-025-00364-w","url":null,"abstract":"MAST-like, or Greatwall (Gwl), an atypical protein kinase related to the evolutionarily conserved MAST kinase family, is crucial for cell cycle control during mitotic entry. Mechanistically, Greatwall is activated by Cyclin B-Cdk1 phosphorylation of a 550 amino acids-long insertion in its atypical activation segment. Subsequently, Gwl phosphorylates Endosulfine and Arpp19 to convert them into inhibitors of PP2A-B55 phosphatase, thereby preventing early dephosphorylation of M-phase targets of Cyclin B-Cdk1. Here, searching for an elusive Gwl-like activity in C. elegans, we show that the single worm MAST kinase, KIN-4, fulfills this function in worms and can functionally replace Greatwall in the heterologous Xenopus system. Compared to Greatwall, the short activation segment of KIN-4 lacks a phosphorylation site, and KIN-4 is active even when produced in E. coli. We also show that a balance between Cyclin B-Cdk1 and PP2A-B55 activity, regulated by KIN-4, is essential to ensure asynchronous cell divisions in the early worm embryo. These findings resolve a long-standing puzzle related to the supposed absence of a Greatwall pathway in C. elegans, and highlight a novel aspect of PP2A-B55 regulation by MAST kinases.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1943-1974"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442655","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

The structure of basal body inner junctions from Tetrahymena revealed by electron cryo-tomography. 电子冷冻断层扫描显示的四膜虫基底内层结结构。

IF 8.3 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-24 DOI: 10.1038/s44318-025-00392-6

Sam Li, Jose-Jesus Fernandez, Marisa D Ruehle, Rachel A Howard-Till, Amy Fabritius, Chad G Pearson, David A Agard, Mark E Winey

{"title":"The structure of basal body inner junctions from Tetrahymena revealed by electron cryo-tomography.","authors":"Sam Li, Jose-Jesus Fernandez, Marisa D Ruehle, Rachel A Howard-Till, Amy Fabritius, Chad G Pearson, David A Agard, Mark E Winey","doi":"10.1038/s44318-025-00392-6","DOIUrl":"10.1038/s44318-025-00392-6","url":null,"abstract":"The cilium is a microtubule-based eukaryotic organelle critical for many cellular functions. Its assembly initiates at a basal body and continues as an axoneme that projects out of the cell to form a functional cilium. This assembly process is tightly regulated. However, our knowledge of the molecular architecture and the mechanism of assembly is limited. By applying cryo-electron tomography, we obtained structures of the inner junction in three regions of the cilium from Tetrahymena: the proximal, the central core of the basal body, and the axoneme. We identified several protein components in the basal body. While a few proteins are distributed throughout the entire length of the organelle, many are restricted to specific regions, forming intricate local interaction networks in the inner junction and bolstering local structural stability. By examining the inner junction in a POC1 knockout mutant, we found the triplet microtubule was destabilized, resulting in a defective structure. Surprisingly, several axoneme-specific components were found to \"infiltrate\" into the mutant basal body. Our findings provide molecular insight into cilium assembly at the inner junctions, underscoring its precise spatial regulation.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1975-2001"},"PeriodicalIF":8.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494526","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

Different Ras isoforms regulate synaptic plasticity in opposite directions. 不同的Ras亚型以相反的方向调节突触的可塑性。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-21 DOI: 10.1038/s44318-025-00390-8

Esperanza López-Merino, Alba Fernández-Rodrigo, Jessie G Jiang, Silvia Gutiérrez-Eisman, David Fernández de Sevilla, Alberto Fernández-Medarde, Eugenio Santos, Carmen Guerra, Mariano Barbacid, José A Esteban, Víctor Briz

{"title":"Different Ras isoforms regulate synaptic plasticity in opposite directions.","authors":"Esperanza López-Merino, Alba Fernández-Rodrigo, Jessie G Jiang, Silvia Gutiérrez-Eisman, David Fernández de Sevilla, Alberto Fernández-Medarde, Eugenio Santos, Carmen Guerra, Mariano Barbacid, José A Esteban, Víctor Briz","doi":"10.1038/s44318-025-00390-8","DOIUrl":"10.1038/s44318-025-00390-8","url":null,"abstract":"The small GTPase Ras is an intracellular signaling hub required for long-term potentiation (LTP) in the hippocampus and for memory formation. Genetic alterations in Ras signaling (i.e., RASopathies) are linked to cognitive disorders in humans. However, it remains unclear how Ras controls synaptic plasticity, and whether different Ras isoforms play overlapping or distinct roles in neurons. Using genetically modified mice, we show here that H-Ras (the most abundant isoform in the brain) does not promote LTP, but instead long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). Mechanistically, H-Ras is activated locally in spines during mGluR-LTD via c-Src, and is required to trigger Erk activation and de novo protein synthesis. Furthermore, H-Ras deletion impairs object recognition as well as social and spatial memory. Conversely, K-Ras is the isoform specifically required for LTP. This functional specialization correlates with a differential synaptic distribution of the two isoforms H-Ras and K-Ras, which may have important implications for RASopathies and cognitive function.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2106-2133"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473192","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

Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides. 人类解偶联蛋白 1 的质子传导受嘌呤和嘧啶核苷酸的抑制。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-28 DOI: 10.1038/s44318-025-00395-3

Scott A Jones, Alice P Sowton, Denis Lacabanne, Martin S King, Shane M Palmer, Thomas Zögg, Els Pardon, Jan Steyaert, Jonathan J Ruprecht, Edmund R S Kunji

{"title":"Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.","authors":"Scott A Jones, Alice P Sowton, Denis Lacabanne, Martin S King, Shane M Palmer, Thomas Zögg, Els Pardon, Jan Steyaert, Jonathan J Ruprecht, Edmund R S Kunji","doi":"10.1038/s44318-025-00395-3","DOIUrl":"10.1038/s44318-025-00395-3","url":null,"abstract":"Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial proton motive force to release energy as heat. Purine nucleotides are considered to be the only inhibitors of UCP1 activity, binding to its central cavity to lock UCP1 in a proton-impermeable conformation. Here we show that pyrimidine nucleotides can also bind and inhibit its proton-conducting activity. All nucleotides bound in a pH-dependent manner, with the highest binding affinity observed for ATP, followed by dTTP, UTP, GTP and CTP. We also determined the structural basis of UTP binding to UCP1, showing that binding of purine and pyrimidine nucleotides follows the same molecular principles. We find that the closely related mitochondrial dicarboxylate carrier (SLC25A10) and oxoglutarate carrier (SLC25A11) have many cavity residues in common, but do not bind nucleotides. Thus, while UCP1 has evolved from dicarboxylate carriers, no selection for nucleobase specificity has occurred, highlighting the importance of the pH-dependent nucleotide binding mechanism mediated via the phosphate moieties.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2353-2365"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532101","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

Author Correction: Drosophila Alms1 proteins regulate centriolar cartwheel assembly by enabling Plk4-Ana2 amplification loop. 作者更正：果蝇Alms1蛋白通过激活Plk4-Ana2扩增环来调节向心轮组装。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 DOI: 10.1038/s44318-025-00411-6

Marine Brunet, Joëlle Thomas, Jean-André Lapart, Léo Krüttli, Marine H Laporte, Maria Giovanna Riparbelli, Giuliano Callaini, Bénédicte Durand, Véronique Morel

引用次数: 0

An epitranscriptomic program maintains skeletal stem cell quiescence via a METTL3-FEM1B-GLI1 axis. 一个表转录组学程序通过METTL3-FEM1B-GLI1轴维持骨骼干细胞的静止。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-04-01 Epub Date: 2025-02-27 DOI: 10.1038/s44318-025-00399-z

Jing Wang, Weidong Liu, Tiantian Zhang, Manman Cui, Kexin Gao, Pengbo Lu, Shuxin Yao, Ziyan Cao, Yanbing Zheng, Wen Tian, Yan Li, Rong Yin, Jin Hu, Guoqiang Han, Jianfei Liang, Fuling Zhou, Jihua Chai, Haojian Zhang

{"title":"An epitranscriptomic program maintains skeletal stem cell quiescence via a METTL3-FEM1B-GLI1 axis.","authors":"Jing Wang, Weidong Liu, Tiantian Zhang, Manman Cui, Kexin Gao, Pengbo Lu, Shuxin Yao, Ziyan Cao, Yanbing Zheng, Wen Tian, Yan Li, Rong Yin, Jin Hu, Guoqiang Han, Jianfei Liang, Fuling Zhou, Jihua Chai, Haojian Zhang","doi":"10.1038/s44318-025-00399-z","DOIUrl":"10.1038/s44318-025-00399-z","url":null,"abstract":"Skeletal stem cells (SSCs) maintain the skeletal system via pluripotency and differentiation capacity. However, it remains largely unknown how these cells precisely regulate their function to maintain skeletal organization. Here, we delineate the RNA m6A modification landscape across skeletal cell populations in the mouse epiphysis. Our findings show that m6A modifications are prevalent in skeletal stem cell and progenitor populations and play critical roles in cell fate determination. Genetic deletion of Mettl3, the core catalytic subunit of the m6A-methyltransferase complex, in murine skeletal stem and progenitors impaired bone development, leading to shortened limbs, disrupted growth plate zonation, and decreased bone mass. Moreover, Mettl3 deficiency induced quiescence exit in SSCs, together with compromised self-renewal capacity and differentiation potential. Mechanistically, Mettl3-mediated m6A modification reduced mRNA stability of the Cul2-RING E3 ligase complex subunit Fem1b, which subsequently stabilizes Gli1 protein, a key transcription factor of Hedgehog pathway for maintaining SSC identity and function. Thus, we present a comprehensive RNA m6A modification landscape of skeletal cell hierarchy and uncover the essential function of epitranscriptomically-regulated proteostasis in maintaining SSCs quiescence and potency.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"2263-2278"},"PeriodicalIF":9.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525046","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