Pub Date : 2024-05-16DOI: 10.1038/s41556-024-01410-1
Melia Granath-Panelo, Shingo Kajimura
Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling. Granath-Panelo and Kajimura review emerging evidence of mitochondrial heterogeneity in different contexts and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.
尽管线粒体是细胞能量需求的中心，但考虑每个细胞如何调整其线粒体组成和功能以适应其 ATP 生产以外的特殊需求正变得越来越重要。在此，我们将深入探讨线粒体在整个发育过程中的异质性以及在具有特定能量需求的组织中的异质性，并讨论线粒体的可塑性如何有助于细胞命运的决定和组织的重塑。Granath-Panelo 和 Kajimura 回顾了不同情况下线粒体异质性的新证据，并讨论了线粒体的可塑性如何有助于细胞命运决定和组织重塑。
{"title":"Mitochondrial heterogeneity and adaptations to cellular needs","authors":"Melia Granath-Panelo, Shingo Kajimura","doi":"10.1038/s41556-024-01410-1","DOIUrl":"10.1038/s41556-024-01410-1","url":null,"abstract":"Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling. Granath-Panelo and Kajimura review emerging evidence of mitochondrial heterogeneity in different contexts and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953244","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}
Pub Date : 2024-05-14DOI: 10.1038/s41556-024-01420-z
Lin Yang, Zhaoru Zhang, Penglei Jiang, Delin Kong, Zebin Yu, Danrong Shi, Yingli Han, Ertuo Chen, Weiyan Zheng, Jie Sun, Yanmin Zhao, Yi Luo, Jimin Shi, Hangping Yao, He Huang, Pengxu Qian
RNA-binding proteins (RBPs) are pivotal in acute myeloid leukaemia (AML), a lethal disease. Although specific phase separation-competent RBPs are recognized in AML, the effect of their condensate formation on AML leukaemogenesis, and the therapeutic potential of inhibition of phase separation are underexplored. In our in vivo CRISPR RBP screen, fibrillarin (FBL) emerges as a crucial nucleolar protein that regulates AML cell survival, primarily through its phase separation domains rather than methyltransferase or acetylation domains. These phase separation domains, with specific features, coordinately drive nucleoli formation and early processing of pre-rRNA (including efflux, cleavage and methylation), eventually enhancing the translation of oncogenes such as MYC. Targeting the phase separation capability of FBL with CGX-635 leads to elimination of AML cells, suggesting an additional mechanism of action for CGX-635 that complements its established therapeutic effects. We highlight the potential of PS modulation of critical proteins as a possible therapeutic strategy for AML. Yang et al. report that the nucleolar protein fibrillarin (FBL) affects acute myeloid leukaemia (AML) cell function through biomolecular condensation-dependent regulation of early pre-rRNA processing and translation.
{"title":"Phase separation-competent FBL promotes early pre-rRNA processing and translation in acute myeloid leukaemia","authors":"Lin Yang, Zhaoru Zhang, Penglei Jiang, Delin Kong, Zebin Yu, Danrong Shi, Yingli Han, Ertuo Chen, Weiyan Zheng, Jie Sun, Yanmin Zhao, Yi Luo, Jimin Shi, Hangping Yao, He Huang, Pengxu Qian","doi":"10.1038/s41556-024-01420-z","DOIUrl":"10.1038/s41556-024-01420-z","url":null,"abstract":"RNA-binding proteins (RBPs) are pivotal in acute myeloid leukaemia (AML), a lethal disease. Although specific phase separation-competent RBPs are recognized in AML, the effect of their condensate formation on AML leukaemogenesis, and the therapeutic potential of inhibition of phase separation are underexplored. In our in vivo CRISPR RBP screen, fibrillarin (FBL) emerges as a crucial nucleolar protein that regulates AML cell survival, primarily through its phase separation domains rather than methyltransferase or acetylation domains. These phase separation domains, with specific features, coordinately drive nucleoli formation and early processing of pre-rRNA (including efflux, cleavage and methylation), eventually enhancing the translation of oncogenes such as MYC. Targeting the phase separation capability of FBL with CGX-635 leads to elimination of AML cells, suggesting an additional mechanism of action for CGX-635 that complements its established therapeutic effects. We highlight the potential of PS modulation of critical proteins as a possible therapeutic strategy for AML. Yang et al. report that the nucleolar protein fibrillarin (FBL) affects acute myeloid leukaemia (AML) cell function through biomolecular condensation-dependent regulation of early pre-rRNA processing and translation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919481","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}
Pub Date : 2024-05-13DOI: 10.1038/s41556-024-01414-x
Ranen Aviner, Ting-Ting Lee, Vincent B. Masto, Kathy H. Li, Raul Andino, Judith Frydman
Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type HTT and mHTT are regulated by a stress-responsive upstream open reading frame and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD. Aviner et al. show that translation and aggregation of Huntingtin (HTT) are regulated by a stress-responsive upstream open reading frame. Mutant HTT depletes translation elongation factor eIF5A, leading to ribosome pausing and collisions.
亨廷顿氏病（Huntington's disease，HD）是由亨廷廷（Huntingtin，HTT）基因中的 CAG 三核苷酸重复扩增引起的一种神经退行性疾病。虽然已知突变型 HTT（mHTT）蛋白会聚集，但聚集与神经毒性之间的联系仍不清楚。在这里，我们发现野生型 HTT 和 mHTT 的翻译和聚集都受上游应激反应开放阅读框的调控，而 polyQ 的扩展会导致翻译终止和释放截短的、易聚集的 mHTT 片段。值得注意的是，我们发现在有症状的 HD 小鼠大脑和培养的 HD 细胞中，mHTT 会消耗翻译延伸因子 eIF5A，从而导致普遍的核糖体暂停和碰撞。eIF5A 的缺失会破坏平衡控制，影响急性应激的恢复。重要的是，抑制翻译起始的药物可以减少过早终止，并减轻 HD 中这种不断升级的核糖毒性压力和功能障碍级联。
{"title":"Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s disease","authors":"Ranen Aviner, Ting-Ting Lee, Vincent B. Masto, Kathy H. Li, Raul Andino, Judith Frydman","doi":"10.1038/s41556-024-01414-x","DOIUrl":"10.1038/s41556-024-01414-x","url":null,"abstract":"Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type HTT and mHTT are regulated by a stress-responsive upstream open reading frame and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD. Aviner et al. show that translation and aggregation of Huntingtin (HTT) are regulated by a stress-responsive upstream open reading frame. Mutant HTT depletes translation elongation factor eIF5A, leading to ribosome pausing and collisions.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915078","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}
Pub Date : 2024-05-07DOI: 10.1038/s41556-024-01416-9
Yechiel Elkabetz
Two new landmark studies use innovative and complementary lineage tracing approaches in human cerebral organoids to reveal symmetric stem cell division and direct neurogenesis of basal radial glial cells to enable cortical growth, expansion and differentiation.
{"title":"It takes two to expand the cortex","authors":"Yechiel Elkabetz","doi":"10.1038/s41556-024-01416-9","DOIUrl":"10.1038/s41556-024-01416-9","url":null,"abstract":"Two new landmark studies use innovative and complementary lineage tracing approaches in human cerebral organoids to reveal symmetric stem cell division and direct neurogenesis of basal radial glial cells to enable cortical growth, expansion and differentiation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845213","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}
Pub Date : 2024-05-07DOI: 10.1038/s41556-024-01409-8
Arthur W. Lambert, Yun Zhang, Robert A. Weinberg
Cancer metastasis is a biologically complex process that remains a major challenge in the oncology clinic, accounting for nearly all of the mortality associated with malignant neoplasms. To establish metastatic growths, carcinoma cells must disseminate from the primary tumour, survive in unfamiliar tissue microenvironments, re-activate programs of proliferation, and escape innate and adaptive immunosurveillance. The entire process is extremely inefficient and can occur over protracted timescales, yielding only a vanishingly small number of carcinoma cells that are able to complete all of the required steps. Here we review both the cancer-cell-intrinsic mechanisms and microenvironmental interactions that enable metastatic colonization. In particular, we highlight recent work on the behaviour of already-disseminated tumour cells, since meaningful progress in treating metastatic disease will clearly require a better understanding of the cells that spawn metastases, which generally have disseminated by the time of initial diagnosis. Metastatic colonization involves cancer-cell-intrinsic mechanisms and microenvironmental interactions, and a better understanding of the factors that influence the final, post-extravasation phases is crucial for therapeutically targeting metatstasis.
{"title":"Cell-intrinsic and microenvironmental determinants of metastatic colonization","authors":"Arthur W. Lambert, Yun Zhang, Robert A. Weinberg","doi":"10.1038/s41556-024-01409-8","DOIUrl":"10.1038/s41556-024-01409-8","url":null,"abstract":"Cancer metastasis is a biologically complex process that remains a major challenge in the oncology clinic, accounting for nearly all of the mortality associated with malignant neoplasms. To establish metastatic growths, carcinoma cells must disseminate from the primary tumour, survive in unfamiliar tissue microenvironments, re-activate programs of proliferation, and escape innate and adaptive immunosurveillance. The entire process is extremely inefficient and can occur over protracted timescales, yielding only a vanishingly small number of carcinoma cells that are able to complete all of the required steps. Here we review both the cancer-cell-intrinsic mechanisms and microenvironmental interactions that enable metastatic colonization. In particular, we highlight recent work on the behaviour of already-disseminated tumour cells, since meaningful progress in treating metastatic disease will clearly require a better understanding of the cells that spawn metastases, which generally have disseminated by the time of initial diagnosis. Metastatic colonization involves cancer-cell-intrinsic mechanisms and microenvironmental interactions, and a better understanding of the factors that influence the final, post-extravasation phases is crucial for therapeutically targeting metatstasis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845067","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}
Pub Date : 2024-05-07DOI: 10.1038/s41556-024-01412-z
Dominik Lindenhofer, Simon Haendeler, Christopher Esk, Jamie B. Littleboy, Clarisse Brunet Avalos, Julia Naas, Florian G. Pflug, Eline G. P. van de Ven, Daniel Reumann, Alexandre D. Baffet, Arndt von Haeseler, Jürgen A. Knoblich
During brain development, neural progenitors expand through symmetric divisions before giving rise to differentiating cell types via asymmetric divisions. Transition between those modes varies among individual neural stem cells, resulting in clones of different sizes. Imaging-based lineage tracing allows for lineage analysis at high cellular resolution but systematic approaches to analyse clonal behaviour of entire tissues are currently lacking. Here we implement whole-tissue lineage tracing by genomic DNA barcoding in 3D human cerebral organoids, to show that individual stem cell clones produce progeny on a vastly variable scale. By using stochastic modelling we find that variable lineage sizes arise because a subpopulation of lineages retains symmetrically dividing cells. We show that lineage sizes can adjust to tissue demands after growth perturbation via chemical ablation or genetic restriction of a subset of cells in chimeric organoids. Our data suggest that adaptive plasticity of stem cell populations ensures robustness of development in human brain organoids. Lindenhofer, Haendeler, Esk, Littleboy et al. perform whole-tissue lineage tracing in human cerebral organoids to reveal that a subpopulation of symmetrically dividing cells can adjust its lineage size depending on tissue demands.
{"title":"Cerebral organoids display dynamic clonal growth and tunable tissue replenishment","authors":"Dominik Lindenhofer, Simon Haendeler, Christopher Esk, Jamie B. Littleboy, Clarisse Brunet Avalos, Julia Naas, Florian G. Pflug, Eline G. P. van de Ven, Daniel Reumann, Alexandre D. Baffet, Arndt von Haeseler, Jürgen A. Knoblich","doi":"10.1038/s41556-024-01412-z","DOIUrl":"10.1038/s41556-024-01412-z","url":null,"abstract":"During brain development, neural progenitors expand through symmetric divisions before giving rise to differentiating cell types via asymmetric divisions. Transition between those modes varies among individual neural stem cells, resulting in clones of different sizes. Imaging-based lineage tracing allows for lineage analysis at high cellular resolution but systematic approaches to analyse clonal behaviour of entire tissues are currently lacking. Here we implement whole-tissue lineage tracing by genomic DNA barcoding in 3D human cerebral organoids, to show that individual stem cell clones produce progeny on a vastly variable scale. By using stochastic modelling we find that variable lineage sizes arise because a subpopulation of lineages retains symmetrically dividing cells. We show that lineage sizes can adjust to tissue demands after growth perturbation via chemical ablation or genetic restriction of a subset of cells in chimeric organoids. Our data suggest that adaptive plasticity of stem cell populations ensures robustness of development in human brain organoids. Lindenhofer, Haendeler, Esk, Littleboy et al. perform whole-tissue lineage tracing in human cerebral organoids to reveal that a subpopulation of symmetrically dividing cells can adjust its lineage size depending on tissue demands.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01412-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845328","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}
Pub Date : 2024-05-07DOI: 10.1038/s41556-024-01418-7
Songzi Liu, Xiaoge Zhang, Xin Yao, Guan Wang, Shijia Huang, Peng Chen, Mingliang Tang, Jie Cai, Zhuyin Wu, Yiliang Zhang, Rongzhi Xu, Kai Liu, Kangmin He, Yan Wang, Lei Jiang, Qiong A. Wang, Liangyou Rui, Jianmiao Liu, Yong Liu
Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α–SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α–XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α–SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity. Liu, Zhang, Yao et al. report that IRE1 α clustering, known to be part of the unfolded protein response, is membrane-bound phase separation and that IRE1 can coalesce with the phase-separated stress granules.
{"title":"Mammalian IRE1α dynamically and functionally coalesces with stress granules","authors":"Songzi Liu, Xiaoge Zhang, Xin Yao, Guan Wang, Shijia Huang, Peng Chen, Mingliang Tang, Jie Cai, Zhuyin Wu, Yiliang Zhang, Rongzhi Xu, Kai Liu, Kangmin He, Yan Wang, Lei Jiang, Qiong A. Wang, Liangyou Rui, Jianmiao Liu, Yong Liu","doi":"10.1038/s41556-024-01418-7","DOIUrl":"10.1038/s41556-024-01418-7","url":null,"abstract":"Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α–SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α–XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α–SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity. Liu, Zhang, Yao et al. report that IRE1 α clustering, known to be part of the unfolded protein response, is membrane-bound phase separation and that IRE1 can coalesce with the phase-separated stress granules.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845087","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}
Pub Date : 2024-05-03DOI: 10.1038/s41556-024-01415-w
Seungbok Yang, Mahdi Golkaram, Seyoun Oh, Yujeong Oh, Yoonjae Cho, Jeehyun Yoe, Sungeun Ju, Matthew A. Lalli, Seung-Yeol Park, Yoontae Lee, Jiwon Jang
Dynamic changes in mechanical microenvironments, such as cell crowding, regulate lineage fates as well as cell proliferation. Although regulatory mechanisms for contact inhibition of proliferation have been extensively studied, it remains unclear how cell crowding induces lineage specification. Here we found that a well-known oncogene, ETS variant transcription factor 4 (ETV4), serves as a molecular transducer that links mechanical microenvironments and gene expression. In a growing epithelium of human embryonic stem cells, cell crowding dynamics is translated into ETV4 expression, serving as a pre-pattern for future lineage fates. A switch-like ETV4 inactivation by cell crowding derepresses the potential for neuroectoderm differentiation in human embryonic stem cell epithelia. Mechanistically, cell crowding inactivates the integrin–actomyosin pathway and blocks the endocytosis of fibroblast growth factor receptors (FGFRs). The disrupted FGFR endocytosis induces a marked decrease in ETV4 protein stability through ERK inactivation. Mathematical modelling demonstrates that the dynamics of cell density in a growing human embryonic stem cell epithelium precisely determines the spatiotemporal ETV4 expression pattern and, consequently, the timing and geometry of lineage development. Our findings suggest that cell crowding dynamics in a stem cell epithelium drives spatiotemporal lineage specification using ETV4 as a key mechanical transducer. Yang, Golkaram et al. reported that in human embryonic stem cells, cellular crowding leads to the blockade of FGFR1 endocytosis, resulting in a decrease in ETV4 expression. This, in turn, derepresses the neuroectoderm fate.
{"title":"ETV4 is a mechanical transducer linking cell crowding dynamics to lineage specification","authors":"Seungbok Yang, Mahdi Golkaram, Seyoun Oh, Yujeong Oh, Yoonjae Cho, Jeehyun Yoe, Sungeun Ju, Matthew A. Lalli, Seung-Yeol Park, Yoontae Lee, Jiwon Jang","doi":"10.1038/s41556-024-01415-w","DOIUrl":"10.1038/s41556-024-01415-w","url":null,"abstract":"Dynamic changes in mechanical microenvironments, such as cell crowding, regulate lineage fates as well as cell proliferation. Although regulatory mechanisms for contact inhibition of proliferation have been extensively studied, it remains unclear how cell crowding induces lineage specification. Here we found that a well-known oncogene, ETS variant transcription factor 4 (ETV4), serves as a molecular transducer that links mechanical microenvironments and gene expression. In a growing epithelium of human embryonic stem cells, cell crowding dynamics is translated into ETV4 expression, serving as a pre-pattern for future lineage fates. A switch-like ETV4 inactivation by cell crowding derepresses the potential for neuroectoderm differentiation in human embryonic stem cell epithelia. Mechanistically, cell crowding inactivates the integrin–actomyosin pathway and blocks the endocytosis of fibroblast growth factor receptors (FGFRs). The disrupted FGFR endocytosis induces a marked decrease in ETV4 protein stability through ERK inactivation. Mathematical modelling demonstrates that the dynamics of cell density in a growing human embryonic stem cell epithelium precisely determines the spatiotemporal ETV4 expression pattern and, consequently, the timing and geometry of lineage development. Our findings suggest that cell crowding dynamics in a stem cell epithelium drives spatiotemporal lineage specification using ETV4 as a key mechanical transducer. Yang, Golkaram et al. reported that in human embryonic stem cells, cellular crowding leads to the blockade of FGFR1 endocytosis, resulting in a decrease in ETV4 expression. This, in turn, derepresses the neuroectoderm fate.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01415-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821114","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}
Pub Date : 2024-04-30DOI: 10.1038/s41556-024-01413-y
Tianchi Xin, Sara Gallini, Haoyang Wei, David G. Gonzalez, Catherine Matte-Martone, Hiroki Machida, Hironobu Fujiwara, H. Amalia Pasolli, Kathleen C. Suozzi, Lauren E. Gonzalez, Sergi Regot, Valentina Greco
Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells’ orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts KrasG12D-induced tissue deformation through modulating specific features of cell migration and division. Xin et al. show, through intravital imaging, that KrasG12D induces epithelial tissue deformation in a spatiotemporally specific manner by converting the pulsatile ERK signal fluctuation in stem cells into sustained activation.
{"title":"Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation","authors":"Tianchi Xin, Sara Gallini, Haoyang Wei, David G. Gonzalez, Catherine Matte-Martone, Hiroki Machida, Hironobu Fujiwara, H. Amalia Pasolli, Kathleen C. Suozzi, Lauren E. Gonzalez, Sergi Regot, Valentina Greco","doi":"10.1038/s41556-024-01413-y","DOIUrl":"10.1038/s41556-024-01413-y","url":null,"abstract":"Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells’ orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts KrasG12D-induced tissue deformation through modulating specific features of cell migration and division. Xin et al. show, through intravital imaging, that KrasG12D induces epithelial tissue deformation in a spatiotemporally specific manner by converting the pulsatile ERK signal fluctuation in stem cells into sustained activation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814523","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}
Pub Date : 2024-04-26DOI: 10.1038/s41556-024-01405-y
Ziwen Li, Yameng Hu, Haiqing Zheng, Man Li, Yuanji Liu, Rongni Feng, Xincheng Li, Shuxia Zhang, Miaoling Tang, Meisongzhu Yang, Ruyuan Yu, Yingru Xu, Xinyi Liao, Suwen Chen, Wanying Qian, Qiliang Zhang, Daolin Tang, Bo Li, Libing Song, Jun Li
The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.
{"title":"LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth","authors":"Ziwen Li, Yameng Hu, Haiqing Zheng, Man Li, Yuanji Liu, Rongni Feng, Xincheng Li, Shuxia Zhang, Miaoling Tang, Meisongzhu Yang, Ruyuan Yu, Yingru Xu, Xinyi Liao, Suwen Chen, Wanying Qian, Qiliang Zhang, Daolin Tang, Bo Li, Libing Song, Jun Li","doi":"10.1038/s41556-024-01405-y","DOIUrl":"10.1038/s41556-024-01405-y","url":null,"abstract":"The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140648684","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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