Advanced atherosclerosis is the pathological basis for acute cardiovascular events, with significant residual risk of recurrent clinical events despite contemporary treatment. The death of foamy macrophages is a main contributor to plaque progression, but the underlying mechanisms remain unclear. Bulk and single-cell RNA sequencing demonstrated that massive iron accumulation in advanced atherosclerosis promoted foamy macrophage ferroptosis, particularly in low expression of triggering receptor expressed on myeloid cells 2 (TREM2low) foamy macrophages. This cluster exhibits metabolic characteristics with low oxidative phosphorylation (OXPHOS), increasing ferroptosis sensitivity. Mechanically, upregulated heme oxygenase 1 (HMOX1)-lactate dehydrogenase B (LDHB) interaction enables Lon peptidase 1 (LONP1) to degrade mitochondrial transcription factor A (TFAM), leading to mitochondrial dysfunction and ferroptosis. Administration of the mitochondria-targeted reactive oxygen species (ROS) scavenger MitoTEMPO (mitochondrial-targeted TEMPO) or LONP1 inhibitor bortezomib restored mitochondrial homeostasis in foamy macrophages and alleviated atherosclerosis. Collectively, our study elucidates the cellular and molecular mechanism of foamy macrophage ferroptosis, offering potential therapeutic strategies for advanced atherosclerosis.
{"title":"HMOX1-LDHB interaction promotes ferroptosis by inducing mitochondrial dysfunction in foamy macrophages during advanced atherosclerosis","authors":"Xiang Peng, Bin Sun, Chaohui Tang, Chengyu Shi, Xianwei Xie, Xueyu Wang, Dingsheng Jiang, Shuo Li, Ying Jia, Yani Wang, Huifang Tang, Shan Zhong, Minghui Piao, Xiuru Cui, Shenghao Zhang, Fan Wang, Yan Wang, Ruisi Na, Renping Huang, Yanan Jiang, Jinwei Tian","doi":"10.1016/j.devcel.2024.12.011","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.011","url":null,"abstract":"Advanced atherosclerosis is the pathological basis for acute cardiovascular events, with significant residual risk of recurrent clinical events despite contemporary treatment. The death of foamy macrophages is a main contributor to plaque progression, but the underlying mechanisms remain unclear. Bulk and single-cell RNA sequencing demonstrated that massive iron accumulation in advanced atherosclerosis promoted foamy macrophage ferroptosis, particularly in low expression of triggering receptor expressed on myeloid cells 2 (TREM2<sup>low</sup>) foamy macrophages. This cluster exhibits metabolic characteristics with low oxidative phosphorylation (OXPHOS), increasing ferroptosis sensitivity. Mechanically, upregulated heme oxygenase 1 (HMOX1)-lactate dehydrogenase B (LDHB) interaction enables Lon peptidase 1 (LONP1) to degrade mitochondrial transcription factor A (TFAM), leading to mitochondrial dysfunction and ferroptosis. Administration of the mitochondria-targeted reactive oxygen species (ROS) scavenger MitoTEMPO (mitochondrial-targeted TEMPO) or LONP1 inhibitor bortezomib restored mitochondrial homeostasis in foamy macrophages and alleviated atherosclerosis. Collectively, our study elucidates the cellular and molecular mechanism of foamy macrophage ferroptosis, offering potential therapeutic strategies for advanced atherosclerosis.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"33 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887881","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 : 2024-12-27DOI: 10.1016/j.devcel.2024.12.010
Pin-Ji Lei, Katarina J. Ruscic, Kangsan Roh, Johanna J. Rajotte, Meghan J. O’Melia, Echoe M. Bouta, Marla Marquez, Ethel R. Pereira, Ashwin S. Kumar, Mohammad S. Razavi, Hengbo Zhou, Lutz Menzel, Liqing Huang, Heena Kumra, Mark Duquette, Peigen Huang, James W. Baish, Lance L. Munn, Natasza A. Kurpios, Jessalyn M. Ubellacker, Timothy P. Padera
Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas—including LMCs—of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.
{"title":"Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice","authors":"Pin-Ji Lei, Katarina J. Ruscic, Kangsan Roh, Johanna J. Rajotte, Meghan J. O’Melia, Echoe M. Bouta, Marla Marquez, Ethel R. Pereira, Ashwin S. Kumar, Mohammad S. Razavi, Hengbo Zhou, Lutz Menzel, Liqing Huang, Heena Kumra, Mark Duquette, Peigen Huang, James W. Baish, Lance L. Munn, Natasza A. Kurpios, Jessalyn M. Ubellacker, Timothy P. Padera","doi":"10.1016/j.devcel.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.010","url":null,"abstract":"Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas—including LMCs—of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"313 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887879","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}
Maintenance and exit from pluripotency of embryonic stem cells (ESCs) are controlled by highly coordinated processes of protein synthesis and ribosome biogenesis (RiBi). ESCs are characterized by low rates of global protein synthesis and high levels of RiBi. Transient reduction of RiBi is a characteristic molecular event during the exit from pluripotency, of which the regulatory mechanism is unclear. Here, we identify that a previously uncharacterized nucleolar protein, pluripotency exit factor (PEXF), encoded by long noncoding RNA LINC00472, plays a role in the transient reduction of RiBi. PEXF dissociates RNA polymerase I from the rDNA through interaction with the rDNA promoter region in a liquid-liquid phase separation-dependent manner, therefore inhibiting the production of pre-ribosomal RNA, a key component of ribosomes. This finding reveals a potential mechanism of exit from pluripotency gated by ribosome levels in human ESCs.
{"title":"Nucleolar protein PEXF controls ribosomal RNA synthesis and pluripotency exit","authors":"Zihao Li, Siwen Chen, Sifang Li, Hua Chao, Wenjun Hao, Shuai Zhang, Zemin Li, Jianru Wang, Xiang Li, Yong Wan, Hui Liu","doi":"10.1016/j.devcel.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.004","url":null,"abstract":"Maintenance and exit from pluripotency of embryonic stem cells (ESCs) are controlled by highly coordinated processes of protein synthesis and ribosome biogenesis (RiBi). ESCs are characterized by low rates of global protein synthesis and high levels of RiBi. Transient reduction of RiBi is a characteristic molecular event during the exit from pluripotency, of which the regulatory mechanism is unclear. Here, we identify that a previously uncharacterized nucleolar protein, pluripotency exit factor (PEXF), encoded by long noncoding RNA <em>LINC00472</em>, plays a role in the transient reduction of RiBi. PEXF dissociates RNA polymerase I from the rDNA through interaction with the rDNA promoter region in a liquid-liquid phase separation-dependent manner, therefore inhibiting the production of pre-ribosomal RNA, a key component of ribosomes. This finding reveals a potential mechanism of exit from pluripotency gated by ribosome levels in human ESCs.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"41 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886696","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 : 2024-12-26DOI: 10.1016/j.devcel.2024.12.005
David Remy, Sandra Antoine-Bally, Sophie de Toqueville, Célia Jolly, Anne-Sophie Macé, Gabriel Champenois, Fariba Nemati, Isabel Brito, Virginie Raynal, Amulya Priya, Adèle Berlioz, Ahmed Dahmani, André Nicolas, Didier Meseure, Elisabetta Marangoni, Philippe Chavrier
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently hyperactivated in triple-negative breast cancers (TNBCs) associated with poor prognosis and is a therapeutic target in breast cancer management. Here, we describe the effects of repression of mTOR-containing complex 1 (mTORC1) through knockdown of several key mTORC1 components or with mTOR inhibitors used in cancer therapy. mTORC1 repression results in an ∼10-fold increase in extracellular matrix proteolytic degradation. Repression in several TNBC models, including in patient-derived xenografts (PDXs), induces nuclear translocation of transcription factor EB (TFEB), which drives a transcriptional program that controls endolysosome function and exocytosis. This response triggers a surge in endolysosomal recycling and the surface exposure of membrane type 1 matrix metalloproteinase (MT1-MMP) associated with invadopodia hyperfunctionality. Furthermore, repression of mTORC1 results in a basal-like breast cancer cell phenotype and disruption of ductal carcinoma in situ (DCIS)-like organization in a tumor xenograft model. Altogether, our data call for revaluation of mTOR inhibitors in breast cancer therapy.
{"title":"TFEB triggers a matrix degradation and invasion program in triple-negative breast cancer cells upon mTORC1 repression","authors":"David Remy, Sandra Antoine-Bally, Sophie de Toqueville, Célia Jolly, Anne-Sophie Macé, Gabriel Champenois, Fariba Nemati, Isabel Brito, Virginie Raynal, Amulya Priya, Adèle Berlioz, Ahmed Dahmani, André Nicolas, Didier Meseure, Elisabetta Marangoni, Philippe Chavrier","doi":"10.1016/j.devcel.2024.12.005","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.005","url":null,"abstract":"The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently hyperactivated in triple-negative breast cancers (TNBCs) associated with poor prognosis and is a therapeutic target in breast cancer management. Here, we describe the effects of repression of mTOR-containing complex 1 (mTORC1) through knockdown of several key mTORC1 components or with mTOR inhibitors used in cancer therapy. mTORC1 repression results in an ∼10-fold increase in extracellular matrix proteolytic degradation. Repression in several TNBC models, including in patient-derived xenografts (PDXs), induces nuclear translocation of transcription factor EB (TFEB), which drives a transcriptional program that controls endolysosome function and exocytosis. This response triggers a surge in endolysosomal recycling and the surface exposure of membrane type 1 matrix metalloproteinase (MT1-MMP) associated with invadopodia hyperfunctionality. Furthermore, repression of mTORC1 results in a basal-like breast cancer cell phenotype and disruption of ductal carcinoma <em>in situ</em> (DCIS)-like organization in a tumor xenograft model. Altogether, our data call for revaluation of mTOR inhibitors in breast cancer therapy.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"31 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887055","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 : 2024-12-26DOI: 10.1016/j.devcel.2024.11.022
Vidur Garg, Yang Yang, Sonja Nowotschin, Manu Setty, Eralda Salataj, Ying-Yi Kuo, Dylan Murphy, Roshan Sharma, Amy Jang, Alexander Polyzos, Dana Pe’er, Effie Apostolou, Anna-Katerina Hadjantonakis
Two distinct lineages, pluripotent epiblast (EPI) and primitive (extra-embryonic) endoderm (PrE), arise from common inner cell mass (ICM) progenitors in mammalian embryos. To study how these sister identities are forged, we leveraged mouse embryonic stem (ES) cells and extra-embryonic endoderm (XEN) stem cells—in vitro counterparts of the EPI and PrE. Bidirectional reprogramming between ES and XEN coupled with single-cell RNA and ATAC-seq analyses showed distinct rates, efficiencies, and trajectories of state conversions, identifying drivers and roadblocks of reciprocal conversions. While GATA4-mediated ES-to-iXEN conversion was rapid and nearly deterministic, OCT4-, KLF4-, and SOX2-induced XEN-to-induced pluripotent stem (iPS) reprogramming progressed with diminished efficiency and kinetics. A dominant PrE transcriptional program, safeguarded by GATA4, alongside elevated chromatin accessibility and reduced DNA methylation of the EPI underscored the differential plasticities of the two states. Mapping in vitro to embryo trajectories tracked reprogramming cells in either direction along EPI and PrE in vivo states, without transitioning through the ICM.
{"title":"Single-cell analysis of bidirectional reprogramming between early embryonic states identify mechanisms of differential lineage plasticities in mice","authors":"Vidur Garg, Yang Yang, Sonja Nowotschin, Manu Setty, Eralda Salataj, Ying-Yi Kuo, Dylan Murphy, Roshan Sharma, Amy Jang, Alexander Polyzos, Dana Pe’er, Effie Apostolou, Anna-Katerina Hadjantonakis","doi":"10.1016/j.devcel.2024.11.022","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.11.022","url":null,"abstract":"Two distinct lineages, pluripotent epiblast (EPI) and primitive (extra-embryonic) endoderm (PrE), arise from common inner cell mass (ICM) progenitors in mammalian embryos. To study how these sister identities are forged, we leveraged mouse embryonic stem (ES) cells and extra-embryonic endoderm (XEN) stem cells—<em>in vitro</em> counterparts of the EPI and PrE. Bidirectional reprogramming between ES and XEN coupled with single-cell RNA and ATAC-seq analyses showed distinct rates, efficiencies, and trajectories of state conversions, identifying drivers and roadblocks of reciprocal conversions. While GATA4-mediated ES-to-iXEN conversion was rapid and nearly deterministic, OCT4-, KLF4-, and SOX2-induced XEN-to-induced pluripotent stem (iPS) reprogramming progressed with diminished efficiency and kinetics. A dominant PrE transcriptional program, safeguarded by GATA4, alongside elevated chromatin accessibility and reduced DNA methylation of the EPI underscored the differential plasticities of the two states. Mapping <em>in vitro</em> to embryo trajectories tracked reprogramming cells in either direction along EPI and PrE <em>in vivo</em> states, without transitioning through the ICM.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"1 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886697","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}
Natural variation is an invaluable genetic resource for plant trait improvement. Here, we performed a genome-wide association study (GWAS) analysis and identified MdHDG5, which controls apple leaf cuticular wax. An A-to-G single-nucleotide polymorphism (SNP) on the HDG5 promoter is associated with HDG5 expression and hexacosanol content (a component of leaf cuticular wax). Furthermore, the single-nucleotide variation (G/G) within a MYB cis-regulatory element (CRE) can be directly bound by MYB62, which represses HDG5 expression and leaf wax deposition. In addition, MdPIAL2, a Small Ubiquitin-like Modifier (SUMO) E3 ligase, positively controls apple leaf wax deposition by stabilizing MdHDG5, while MdMIEL1 interacts with and degrades both MdHDG5 and MdPIAL2 to negatively control leaf wax deposition. Notably, MIEL1 expression is negatively associated with leaf hexacosanol deposition. Taken together, our results provide significant genetic insights into the natural variation of leaf cuticular wax loads in apple and identify the intricate molecular regulation of MdHDG5.
{"title":"Natural variation in an HD-ZIP factor identifies its role in controlling apple leaf cuticular wax deposition","authors":"Fuguo Cao, Qian Qian, Zhongxing Li, Jingrong Wang, Zeyuan Liu, Zitong Zhang, Chundong Niu, Yinpeng Xie, Fengwang Ma, Qingmei Guan","doi":"10.1016/j.devcel.2024.12.001","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.001","url":null,"abstract":"Natural variation is an invaluable genetic resource for plant trait improvement. Here, we performed a genome-wide association study (GWAS) analysis and identified MdHDG5, which controls apple leaf cuticular wax. An A-to-G single-nucleotide polymorphism (SNP) on the <em>HDG5</em> promoter is associated with <em>HDG5</em> expression and hexacosanol content (a component of leaf cuticular wax). Furthermore, the single-nucleotide variation (G/G) within a MYB <em>cis</em>-regulatory element (CRE) can be directly bound by MYB62, which represses <em>HDG5</em> expression and leaf wax deposition. In addition, MdPIAL2, a Small Ubiquitin-like Modifier (SUMO) E3 ligase, positively controls apple leaf wax deposition by stabilizing MdHDG5, while MdMIEL1 interacts with and degrades both MdHDG5 and MdPIAL2 to negatively control leaf wax deposition. Notably, <em>MIEL1</em> expression is negatively associated with leaf hexacosanol deposition. Taken together, our results provide significant genetic insights into the natural variation of leaf cuticular wax loads in apple and identify the intricate molecular regulation of MdHDG5.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"113 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880112","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 : 2024-12-24DOI: 10.1016/j.devcel.2024.12.003
Daniel J. Salas-Escabillas, Megan T. Hoffman, Sydney M. Brender, Jacee S. Moore, Hui-Ju Wen, Simone Benitz, Erick T. Davis, Daniel Long, Allison M. Wombwell, Ella Rose D. Chianis, Brittany L. Allen-Petersen, Nina G. Steele, Rosalie C. Sears, Ichiro Matsumoto, Kathleen E. DelGiorno, Howard C. Crawford
Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplasia, which progresses to neoplasia and cancer. Tuft cells (TCs) are chemosensory cells not found in the normal pancreas but arise in cancer precursor lesions and diminish during progression to carcinoma. These metaplastic TCs (mTCs) suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we created a dual recombinase lineage trace model, wherein a pancreas-specific FlpO was used to induce tumorigenesis, while a tuft-cell specific Pou2f3CreERT/+ driver was used to induce expression of a tdTomato reporter. We found that mTCs in carcinoma transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in patients. Using conditional knockout and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this tuft-to-neuroendocrine transition (TNT).
{"title":"Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer","authors":"Daniel J. Salas-Escabillas, Megan T. Hoffman, Sydney M. Brender, Jacee S. Moore, Hui-Ju Wen, Simone Benitz, Erick T. Davis, Daniel Long, Allison M. Wombwell, Ella Rose D. Chianis, Brittany L. Allen-Petersen, Nina G. Steele, Rosalie C. Sears, Ichiro Matsumoto, Kathleen E. DelGiorno, Howard C. Crawford","doi":"10.1016/j.devcel.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.003","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplasia, which progresses to neoplasia and cancer. Tuft cells (TCs) are chemosensory cells not found in the normal pancreas but arise in cancer precursor lesions and diminish during progression to carcinoma. These metaplastic TCs (mTCs) suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we created a dual recombinase lineage trace model, wherein a pancreas-specific FlpO was used to induce tumorigenesis, while a tuft-cell specific Pou2f3<sup>CreERT/+</sup> driver was used to induce expression of a tdTomato reporter. We found that mTCs in carcinoma transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in patients. Using conditional knockout and overexpression systems, we found that <em>Myc</em> activity in mTCs is necessary and sufficient to induce this tuft-to-neuroendocrine transition (TNT).","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"20 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880238","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 : 2024-12-24DOI: 10.1016/j.devcel.2024.12.002
Fergus Tollervey, Manolo U. Rios, Evgenia Zagoriy, Jeffrey B. Woodruff, Julia Mahamid
Centrosomes organize microtubules that are essential for mitotic divisions in animal cells. They consist of centrioles surrounded by pericentriolar material (PCM). Questions related to mechanisms of centriole assembly, PCM organization, and spindle microtubule formation remain unanswered, partly due to limited availability of molecular-resolution structural data inside cells. Here, we use cryo-electron tomography to visualize centrosomes across the cell cycle in cells isolated from C. elegans embryos. We describe a pseudo-timeline of centriole assembly and identify distinct structural features in both mother and daughter centrioles. We find that centrioles and PCM microtubules differ in protofilament number (13 versus 11), which could be explained by atypical γ-tubulin ring complexes with 11-fold symmetry identified at the minus ends of short PCM microtubule segments. We further characterize a porous and disordered network that forms the interconnected PCM. Thus, our work builds a three-dimensional structural atlas that helps explain how centrosomes assemble, grow, and achieve function.
{"title":"Molecular architectures of centrosomes in C. elegans embryos visualized by cryo-electron tomography","authors":"Fergus Tollervey, Manolo U. Rios, Evgenia Zagoriy, Jeffrey B. Woodruff, Julia Mahamid","doi":"10.1016/j.devcel.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.002","url":null,"abstract":"Centrosomes organize microtubules that are essential for mitotic divisions in animal cells. They consist of centrioles surrounded by pericentriolar material (PCM). Questions related to mechanisms of centriole assembly, PCM organization, and spindle microtubule formation remain unanswered, partly due to limited availability of molecular-resolution structural data inside cells. Here, we use cryo-electron tomography to visualize centrosomes across the cell cycle in cells isolated from <em>C. elegans</em> embryos. We describe a pseudo-timeline of centriole assembly and identify distinct structural features in both mother and daughter centrioles. We find that centrioles and PCM microtubules differ in protofilament number (13 versus 11), which could be explained by atypical γ-tubulin ring complexes with 11-fold symmetry identified at the minus ends of short PCM microtubule segments. We further characterize a porous and disordered network that forms the interconnected PCM. Thus, our work builds a three-dimensional structural atlas that helps explain how centrosomes assemble, grow, and achieve function.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"24 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880108","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 : 2024-12-19DOI: 10.1016/j.devcel.2024.11.021
Sural K. Ranamukhaarachchi, Alyssa Walker, Man-Ho Tang, William D. Leineweber, Sophia Lam, Wouter-Jan Rappel, Stephanie I. Fraley
The coordinated movement of cell collectives is essential for normal epithelial tissue development, maintenance, and cancer progression. Here, we report on a minimal 3D extracellular matrix (ECM) system wherein both invasive collective migration (ICM) and rotational collective migration (RCM) arise spontaneously from individually seeded epithelial cells of mammary and hepatic origin, regardless of whether they express adherens junctions, and lead to ductal-like and acinar-like structures, respectively. Quantitative microscopy and cellular Potts modeling reveal that initial differences in cell protrusion dynamics and matrix-remodeling localization generate RCM and ICM behavior in confining 3D ECM. Matrix-remodeling activity by matrix metalloproteinases (MMPs) is localized to the base of protrusions in cells that initiate ICM, whereas RCM does not require MMPs and is associated with ITGβ1-mediated remodeling localized globally around the cell body. Further analysis in vitro and in vivo supports the concept that distinct matrix-remodeling strategies encode collective migration behaviors and tissue structure.
{"title":"Global versus local matrix remodeling drives rotational versus invasive collective migration of epithelial cells","authors":"Sural K. Ranamukhaarachchi, Alyssa Walker, Man-Ho Tang, William D. Leineweber, Sophia Lam, Wouter-Jan Rappel, Stephanie I. Fraley","doi":"10.1016/j.devcel.2024.11.021","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.11.021","url":null,"abstract":"The coordinated movement of cell collectives is essential for normal epithelial tissue development, maintenance, and cancer progression. Here, we report on a minimal 3D extracellular matrix (ECM) system wherein both invasive collective migration (ICM) and rotational collective migration (RCM) arise spontaneously from individually seeded epithelial cells of mammary and hepatic origin, regardless of whether they express adherens junctions, and lead to ductal-like and acinar-like structures, respectively. Quantitative microscopy and cellular Potts modeling reveal that initial differences in cell protrusion dynamics and matrix-remodeling localization generate RCM and ICM behavior in confining 3D ECM. Matrix-remodeling activity by matrix metalloproteinases (MMPs) is localized to the base of protrusions in cells that initiate ICM, whereas RCM does not require MMPs and is associated with ITGβ1-mediated remodeling localized globally around the cell body. Further analysis <em>in vitro</em> and <em>in vivo</em> supports the concept that distinct matrix-remodeling strategies encode collective migration behaviors and tissue structure.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"113 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849565","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}
In plants, small peptides are important players in the plant stress response, yet their function in plant antiviral responses remains poorly understood. Here, we identify that the plant small peptide, CLAVATA3/ESR-RELATED 7 (CLE7), enhances plant resistance to Chinese wheat mosaic virus infection in Nicotiana (N.) benthamiana. Subsequent investigations demonstrate that CLE7 recognizes receptor kinase NbPXC3 to control the plant antiviral response. Moreover, CLE7-NbPXC3 signaling induces NbMKK2-controlled NbMPK4 phosphorylation, resulting in phosphorylation of the transcription factor NbEDT1. NbEDT1 phosphorylation is involved in the transcriptional activity of NbNCED3, which is a rate-limiting enzyme in abscisic acid (ABA) biosynthesis. Moreover, CLE7 activates broad-spectrum disease resistance to multiple RNA viral infections. Our study indicates that CLE7 induces a plant antiviral response through a series of immune signal transductions in N. benthamiana and provides a foundation for the exploration of efficient viral disease management methods based on plant small peptides.
{"title":"The plant signal peptide CLE7 induces plant defense response against viral infection in Nicotiana benthamiana","authors":"Peng Liu, Juan Zhang, Shuang Liu, Yaoyao Li, Chunyan Qi, Qitao Mo, Yaoyao Jiang, Haichao Hu, Tianye Zhang, Kaili Zhong, Jianqian Liu, Qiansheng Liao, Jianping Chen, Jian Yang","doi":"10.1016/j.devcel.2024.11.020","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.11.020","url":null,"abstract":"In plants, small peptides are important players in the plant stress response, yet their function in plant antiviral responses remains poorly understood. Here, we identify that the plant small peptide, CLAVATA3/ESR-RELATED 7 (CLE7), enhances plant resistance to Chinese wheat mosaic virus infection in <em>Nicotiana (N.) benthamiana</em>. Subsequent investigations demonstrate that CLE7 recognizes receptor kinase NbPXC3 to control the plant antiviral response. Moreover, CLE7-NbPXC3 signaling induces NbMKK2-controlled NbMPK4 phosphorylation, resulting in phosphorylation of the transcription factor NbEDT1. NbEDT1 phosphorylation is involved in the transcriptional activity of <em>NbNCED3</em>, which is a rate-limiting enzyme in abscisic acid (ABA) biosynthesis. Moreover, CLE7 activates broad-spectrum disease resistance to multiple RNA viral infections. Our study indicates that CLE7 induces a plant antiviral response through a series of immune signal transductions in <em>N. benthamiana</em> and provides a foundation for the exploration of efficient viral disease management methods based on plant small peptides.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"28 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825708","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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