Xinyang Li,Yue Hua,Jiahui Wang,Mengxiao Wu,Yu Pan,Jiyong Wang,Xiaoqing Gan
After translation, low-density lipoprotein receptor-related protein 5/6, LRP5/6, are transported from ER through Golgi to cell surface, where they serve as the co-receptors of Wnt proteins to elicit the WNT/β-catenin signaling. Here, Golgi-resident β-1, 4-galactosyltransferase B4GALT1 is revealed to interact with LRP5/6, causing the Golgi retention of LRP5/6 and ultimately reducing LRP5/6 on the cell surface. In addition to LRP5/6, B4GALT1 can also bind to the exclusive Wnt transporter Wntless. Interestingly, this interaction does not affect the Wnt secretion but participates in the LRP5/6 Golgi-retention mediated by B4GALT1. On the other hand, the Wnt secretion that occupies Wntless antagonizes the B4GALT1-mediated LRP5/6 retention on the Golgi apparatus. Accordingly, LGK974-targeted uncoupling of the Wnt/Wntless complex is able to enhance LRP5/6 Golgi retention, thereby attenuating LRP5/6 cell surface translocation. Taken together, the surface presentation of LRP5/6 is regulated by the Golgi-resident B4GALT1 as well as the Wnt secretion activity.
{"title":"B4GALT1 and Wntless collaborate to block LRP5/6 translocation from Golgi to cell surface.","authors":"Xinyang Li,Yue Hua,Jiahui Wang,Mengxiao Wu,Yu Pan,Jiyong Wang,Xiaoqing Gan","doi":"10.1083/jcb.202501170","DOIUrl":"https://doi.org/10.1083/jcb.202501170","url":null,"abstract":"After translation, low-density lipoprotein receptor-related protein 5/6, LRP5/6, are transported from ER through Golgi to cell surface, where they serve as the co-receptors of Wnt proteins to elicit the WNT/β-catenin signaling. Here, Golgi-resident β-1, 4-galactosyltransferase B4GALT1 is revealed to interact with LRP5/6, causing the Golgi retention of LRP5/6 and ultimately reducing LRP5/6 on the cell surface. In addition to LRP5/6, B4GALT1 can also bind to the exclusive Wnt transporter Wntless. Interestingly, this interaction does not affect the Wnt secretion but participates in the LRP5/6 Golgi-retention mediated by B4GALT1. On the other hand, the Wnt secretion that occupies Wntless antagonizes the B4GALT1-mediated LRP5/6 retention on the Golgi apparatus. Accordingly, LGK974-targeted uncoupling of the Wnt/Wntless complex is able to enhance LRP5/6 Golgi retention, thereby attenuating LRP5/6 cell surface translocation. Taken together, the surface presentation of LRP5/6 is regulated by the Golgi-resident B4GALT1 as well as the Wnt secretion activity.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"1 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433707","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}
Monica Dam,David F Moreno,Nicola Brownlow,Audrey Furst,Coralie Spiegelhalter,Manuel Mendoza
The coordination of chromosome segregation with cytokinesis is crucial for maintaining genomic stability. Chromatin bridges, arising from DNA replication stress or catenated chromosomes, can interfere with this process, leading to genomic instability if not properly resolved. Here, we uncover that the budding yeast DNA helicase Srs2 is essential for delaying abscission in the presence of chromatin bridges, thereby preventing chromosome breakage during cytokinesis. We also find that its human paralog PARI delays abscission-associated events, including midbody severing and actin-patch disassembly, in human cells with chromatin bridges. Although PARI depletion does not lead to increased bridge breakage or binucleation, our data indicate that PARI has nonessential functions within the Aurora B-mediated abscission checkpoint pathway. These findings establish a key role of Srs2 in NoCut checkpoint signaling in yeast, and suggest a functionally related role of PARI in coordinating abscission timing with chromatin bridge resolution in human cells.
{"title":"Roles of Srs2/PARI-family DNA helicases in NoCut checkpoint signaling and abscission regulation.","authors":"Monica Dam,David F Moreno,Nicola Brownlow,Audrey Furst,Coralie Spiegelhalter,Manuel Mendoza","doi":"10.1083/jcb.202502014","DOIUrl":"https://doi.org/10.1083/jcb.202502014","url":null,"abstract":"The coordination of chromosome segregation with cytokinesis is crucial for maintaining genomic stability. Chromatin bridges, arising from DNA replication stress or catenated chromosomes, can interfere with this process, leading to genomic instability if not properly resolved. Here, we uncover that the budding yeast DNA helicase Srs2 is essential for delaying abscission in the presence of chromatin bridges, thereby preventing chromosome breakage during cytokinesis. We also find that its human paralog PARI delays abscission-associated events, including midbody severing and actin-patch disassembly, in human cells with chromatin bridges. Although PARI depletion does not lead to increased bridge breakage or binucleation, our data indicate that PARI has nonessential functions within the Aurora B-mediated abscission checkpoint pathway. These findings establish a key role of Srs2 in NoCut checkpoint signaling in yeast, and suggest a functionally related role of PARI in coordinating abscission timing with chromatin bridge resolution in human cells.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"47 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411610","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}
Xin Wang,Ruijun Shi,Yuqing Xiang,Yajing Gao,Guoqiang Wan,Shan Sun,Dong Liu
One of the most basic principles in embryonic development is ensuring the proper size of tissues and organs to meet functional needs. So far, an endogenous metabolite regulating organ size has not been described. The current study highlights itaconate, the product of Irg1, in regulating zebrafish neuromast size. Single-cell transcriptomic sequencing analysis of enzymes catalyzing metabolic processes revealed that irg1l, a homolog of Irg1, is highly expressed in supporting cells of developing neuromast in zebrafish. Deficiency of irg1l reduced the size of the neuromast and caused auditory dysfunction. Conversely, overexpression of irg1l resulted in increased size due to excessive proliferation of supporting cells. Notably, 4-octyl itaconate (4-OI), an itaconate derivative, treatment recapitulates the phenotype of irg1l overexpression and increases the neuromast size. Finally, we revealed that the Irg1l/itaconate axis induces metabolic reprogramming to promote activation of the Yap, drive supporting cell proliferation, and enlarge neuromast size. These findings provide a novel insight into the role of metabolites in organ development.
{"title":"Irg1l regulates neuromast size via metabolic reprogramming to promote supporting cell proliferation.","authors":"Xin Wang,Ruijun Shi,Yuqing Xiang,Yajing Gao,Guoqiang Wan,Shan Sun,Dong Liu","doi":"10.1083/jcb.202501122","DOIUrl":"https://doi.org/10.1083/jcb.202501122","url":null,"abstract":"One of the most basic principles in embryonic development is ensuring the proper size of tissues and organs to meet functional needs. So far, an endogenous metabolite regulating organ size has not been described. The current study highlights itaconate, the product of Irg1, in regulating zebrafish neuromast size. Single-cell transcriptomic sequencing analysis of enzymes catalyzing metabolic processes revealed that irg1l, a homolog of Irg1, is highly expressed in supporting cells of developing neuromast in zebrafish. Deficiency of irg1l reduced the size of the neuromast and caused auditory dysfunction. Conversely, overexpression of irg1l resulted in increased size due to excessive proliferation of supporting cells. Notably, 4-octyl itaconate (4-OI), an itaconate derivative, treatment recapitulates the phenotype of irg1l overexpression and increases the neuromast size. Finally, we revealed that the Irg1l/itaconate axis induces metabolic reprogramming to promote activation of the Yap, drive supporting cell proliferation, and enlarge neuromast size. These findings provide a novel insight into the role of metabolites in organ development.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"1 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373843","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}
Key aspects of osteoclast fusion and its coupling with bone resorption activity are lacking. In this issue, Dufrancias and colleagues (https://doi.org/10.1083/jcb.202409169) shed new light on the mechanism underpinning osteoclast fusion and activity, highlighting the critical role of the ERM family member moesin in this important process.
{"title":"Moesin strikes an \"Actin\"g balance to regulate osteoclast fusion and activity.","authors":"Marwa Zeyad,Yousef Abu-Amer","doi":"10.1083/jcb.202509068","DOIUrl":"https://doi.org/10.1083/jcb.202509068","url":null,"abstract":"Key aspects of osteoclast fusion and its coupling with bone resorption activity are lacking. In this issue, Dufrancias and colleagues (https://doi.org/10.1083/jcb.202409169) shed new light on the mechanism underpinning osteoclast fusion and activity, highlighting the critical role of the ERM family member moesin in this important process.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"1 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370645","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}
Erika Riederer,Vedrana Mikusevic,Tuoxian Tang,Lillian Martin,Joseph A Mindell,Dejian Ren
The acidic pH of lysosomes required for function is established by the electrogenic V-ATPase proton pump. How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson's disease (PD)-associated protein TMEM175 was proposed as a H+-selective channel to leak protons to counter over-acidification. We rigorously address key findings and predictions of this model and show that, in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective channel. The native lysosomal H+ leak is remarkably small, ∼0.02 fA, strongly arguing against major contributions from an ion channel. The predominant effect of TMEM175 deficiencies is lysosomal alkalinization in challenged cells, which is further evidence arguing against TMEM175 as a H+-selective channel and can be explained by K+ conductance through TMEM175. Also, lysosomes can be hyper-acidified by manipulations in the presence or absence of TMEM175. Our studies clarify a basic lysosomal biological problem and provide insights into the working mechanism of TMEM175 and its contribution to PD pathology.
{"title":"TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.","authors":"Erika Riederer,Vedrana Mikusevic,Tuoxian Tang,Lillian Martin,Joseph A Mindell,Dejian Ren","doi":"10.1083/jcb.202501145","DOIUrl":"https://doi.org/10.1083/jcb.202501145","url":null,"abstract":"The acidic pH of lysosomes required for function is established by the electrogenic V-ATPase proton pump. How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson's disease (PD)-associated protein TMEM175 was proposed as a H+-selective channel to leak protons to counter over-acidification. We rigorously address key findings and predictions of this model and show that, in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective channel. The native lysosomal H+ leak is remarkably small, ∼0.02 fA, strongly arguing against major contributions from an ion channel. The predominant effect of TMEM175 deficiencies is lysosomal alkalinization in challenged cells, which is further evidence arguing against TMEM175 as a H+-selective channel and can be explained by K+ conductance through TMEM175. Also, lysosomes can be hyper-acidified by manipulations in the presence or absence of TMEM175. Our studies clarify a basic lysosomal biological problem and provide insights into the working mechanism of TMEM175 and its contribution to PD pathology.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"50 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351653","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}
Trisomy of chromosome 12 is frequently observed across many pluripotent stem cell lines. In this issue, Narozna et al. (https://doi.org/10.1083/jcb.202501231) reveal that trisomy 12 in human-induced pluripotent stem cells (iPSCs) is driven by ongoing missegregation events due to sub-telomeric erosion, which, coupled with a modest growth advantage, results in rapid population takeover.
{"title":"Beyond selection: How chromosome 12 gain dominates stem cell genomes.","authors":"Orléna Benamozig,Ofer Shoshani","doi":"10.1083/jcb.202510048","DOIUrl":"https://doi.org/10.1083/jcb.202510048","url":null,"abstract":"Trisomy of chromosome 12 is frequently observed across many pluripotent stem cell lines. In this issue, Narozna et al. (https://doi.org/10.1083/jcb.202501231) reveal that trisomy 12 in human-induced pluripotent stem cells (iPSCs) is driven by ongoing missegregation events due to sub-telomeric erosion, which, coupled with a modest growth advantage, results in rapid population takeover.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"53 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338701","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}
IQSEC2, a high-confidence neurodevelopmental disorder risk gene product, is essential for neuronal development and synaptic plasticity. Previous studies established that IQSEC2 dynamically regulates synaptic signaling via Ca2+-dependent release of autoinhibition. In this study, using in vivo mouse models and in vitro biochemistry approaches, we discover that IQSEC2 orchestrates postsynaptic density assembly and dynamics via Ca2+-triggered phase separation. Mechanistically, Ca2+-induced conformational opening leads to phase separation-mediated condensation of IQSEC2 at synapses, a process that requires the N-terminal multimerization domain and intrinsically disordered regions of IQSEC2. We identified a single-point mutation, F367A, in IQSEC2, which exhibits constitutive activity by structurally mimicking the Ca2+-activated state of the WT protein. Mice carrying the Iqsec2_F367A mutation have elevated basal synaptic transmission and impaired activity-dependent plasticity assayed in hippocampal neurons and spatial learning deficits. Thus, IQSEC2 can bidirectionally modulate synaptic strengths via Ca2+-dependent phase separation, and dysregulation of phase separation may be a contributing factor in IQSEC2-related neurodevelopmental disorders.
{"title":"IQSEC2/BRAG1 may modulate postsynaptic density assembly through Ca2+-induced phase separation.","authors":"Guanhua Bai,Ruifeng Huang,Xinyue Nan,Mengru Zhuang,Meiling Wu,Yinmiao Lian,Qixu Cai,Honglei Tian,Youming Lu,Hao Li,Mingjie Zhang","doi":"10.1083/jcb.202503076","DOIUrl":"https://doi.org/10.1083/jcb.202503076","url":null,"abstract":"IQSEC2, a high-confidence neurodevelopmental disorder risk gene product, is essential for neuronal development and synaptic plasticity. Previous studies established that IQSEC2 dynamically regulates synaptic signaling via Ca2+-dependent release of autoinhibition. In this study, using in vivo mouse models and in vitro biochemistry approaches, we discover that IQSEC2 orchestrates postsynaptic density assembly and dynamics via Ca2+-triggered phase separation. Mechanistically, Ca2+-induced conformational opening leads to phase separation-mediated condensation of IQSEC2 at synapses, a process that requires the N-terminal multimerization domain and intrinsically disordered regions of IQSEC2. We identified a single-point mutation, F367A, in IQSEC2, which exhibits constitutive activity by structurally mimicking the Ca2+-activated state of the WT protein. Mice carrying the Iqsec2_F367A mutation have elevated basal synaptic transmission and impaired activity-dependent plasticity assayed in hippocampal neurons and spatial learning deficits. Thus, IQSEC2 can bidirectionally modulate synaptic strengths via Ca2+-dependent phase separation, and dysregulation of phase separation may be a contributing factor in IQSEC2-related neurodevelopmental disorders.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"129 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338697","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}
László Fazekas,Diána Kaszás,Boldizsár Vámosi,Szimonetta Xénia Tamás,Tamás Szöllősi,Vivien Mihályi,Fabian Gregor Dehne,Klaudia Vágó-Kiss,Nada Mohamed Al-Sheraji,Barnabás Paulovits,Benoit Thomas Roux,Balázs Enyedi
Fibroblasts are pivotal in tissue homeostasis, contributing to tissue repair and environmental sensing. Studying their role in zebrafish has been hampered by the lack of robust transgene expression tools. Here, we developed a fin fibroblast-specific synthetic promoter by combining the zebrafish itga11a regulatory region with the murine cFos minimal promoter. Establishing this itga11a-cFos promoter in the QF2-QUAS system enabled evaluation of damage-induced signaling pathways in fibroblasts using genetically encoded biosensors. Our findings reveal that fibroblasts generate spatially distinct, sustained calcium signals in response to epithelial injury, in contrast to transient oscillatory signals in keratinocytes. These calcium signals are modulated by external osmotic cues, highlighting a role for fibroblasts in osmotic surveillance. We also show that tissue damage activates the cPla2-mediated shape-sensing and nuclear swelling-dependent pathways in fibroblasts. Our results demonstrate the versatility of the itga11a-cFos promoter in driving fibroblast-specific expression of biosensors and ablation tools. Using this toolkit, we provide new insights into damage-induced signaling pathways in fibroblasts.
{"title":"Fibroblasts promote osmotic surveillance by wound-induced unique calcium patterns.","authors":"László Fazekas,Diána Kaszás,Boldizsár Vámosi,Szimonetta Xénia Tamás,Tamás Szöllősi,Vivien Mihályi,Fabian Gregor Dehne,Klaudia Vágó-Kiss,Nada Mohamed Al-Sheraji,Barnabás Paulovits,Benoit Thomas Roux,Balázs Enyedi","doi":"10.1083/jcb.202501165","DOIUrl":"https://doi.org/10.1083/jcb.202501165","url":null,"abstract":"Fibroblasts are pivotal in tissue homeostasis, contributing to tissue repair and environmental sensing. Studying their role in zebrafish has been hampered by the lack of robust transgene expression tools. Here, we developed a fin fibroblast-specific synthetic promoter by combining the zebrafish itga11a regulatory region with the murine cFos minimal promoter. Establishing this itga11a-cFos promoter in the QF2-QUAS system enabled evaluation of damage-induced signaling pathways in fibroblasts using genetically encoded biosensors. Our findings reveal that fibroblasts generate spatially distinct, sustained calcium signals in response to epithelial injury, in contrast to transient oscillatory signals in keratinocytes. These calcium signals are modulated by external osmotic cues, highlighting a role for fibroblasts in osmotic surveillance. We also show that tissue damage activates the cPla2-mediated shape-sensing and nuclear swelling-dependent pathways in fibroblasts. Our results demonstrate the versatility of the itga11a-cFos promoter in driving fibroblast-specific expression of biosensors and ablation tools. Using this toolkit, we provide new insights into damage-induced signaling pathways in fibroblasts.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"100 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338696","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}
Ana M Dias Maia Henriques,Timothy R Davies,Serge Dmitrieff,Nicolas Minc,Julie C Canman,Julien Dumont,Gilliane Maton
Chromosome segregation during anaphase occurs through two mechanistically distinct processes: anaphase A, in which chromosomes move toward spindle poles, and anaphase B, in which the anaphase spindle elongates through cortical astral microtubule pulling forces. Caenorhabditis elegans embryos have been thought to rely primarily on anaphase B, with little to no contribution from anaphase A. Here, we uncover a novel anaphase A mechanism in C. elegans embryos, driven by the kinesin-13 KLP-7MCAK and opposed by the kinesin-12 KLP-18. We found that the extent of chromosome segregation during anaphase A is asymmetrically regulated by cell polarity cues and modulated by mechanical tension within the spindle, generated by opposing forces acting on chromosomes and spindle poles. Additionally, we found that the contribution of anaphase A to chromosome segregation increases progressively across early embryonic divisions. These findings uncover an unexpected role for anaphase A in early C. elegans development and reveal a KLP-7MCAK-dependent mechanical coordination between anaphase A- and anaphase B-driven chromosome segregation.
{"title":"Mechanical coordination between anaphase A and B drives asymmetric chromosome segregation.","authors":"Ana M Dias Maia Henriques,Timothy R Davies,Serge Dmitrieff,Nicolas Minc,Julie C Canman,Julien Dumont,Gilliane Maton","doi":"10.1083/jcb.202505038","DOIUrl":"https://doi.org/10.1083/jcb.202505038","url":null,"abstract":"Chromosome segregation during anaphase occurs through two mechanistically distinct processes: anaphase A, in which chromosomes move toward spindle poles, and anaphase B, in which the anaphase spindle elongates through cortical astral microtubule pulling forces. Caenorhabditis elegans embryos have been thought to rely primarily on anaphase B, with little to no contribution from anaphase A. Here, we uncover a novel anaphase A mechanism in C. elegans embryos, driven by the kinesin-13 KLP-7MCAK and opposed by the kinesin-12 KLP-18. We found that the extent of chromosome segregation during anaphase A is asymmetrically regulated by cell polarity cues and modulated by mechanical tension within the spindle, generated by opposing forces acting on chromosomes and spindle poles. Additionally, we found that the contribution of anaphase A to chromosome segregation increases progressively across early embryonic divisions. These findings uncover an unexpected role for anaphase A in early C. elegans development and reveal a KLP-7MCAK-dependent mechanical coordination between anaphase A- and anaphase B-driven chromosome segregation.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"2 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339429","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}
The Mos kinase activates the ERK/MAPK pathway during oocyte meiosis, controlling essential meiotic functions in species across metazoa. However, despite its significance, the molecular targets of Mos-MAPK remain largely unidentified. Here, we addressed this question using starfish oocytes ideally suited to combine cellular assays with phosphoproteomics. This revealed CPE-mediated mRNA polyadenylation as a prominent target of Mos-MAPK, and we show that translation is required to drive the second meiotic division. Secondly, we identify a well-defined subset of cytoskeletal regulators as targets of Mos-MAPK. We show that this regulation is critical to ensure the asymmetry of meiotic divisions, primarily by reducing the growth of astral microtubules. This allows positioning of the spindle directly beneath the cortex and prevents the separation of spindle poles in anaphase, thereby minimizing polar body size. Thus, by phosphoproteomics, we reveal molecular modules controlled by Mos-MAPK, explaining how this single, conserved kinase can act as a switch between the mitotic and meiotic division programs.
{"title":"Phosphoproteomic identification of Mos-MAPK targets in meiotic cell cycle and asymmetric oocyte divisions.","authors":"Ivan Avilov,Yehor Horokhovskyi,Pooja Mehta,Luisa Welp,Jasmin Jakobi,Mingfang Cai,Aleksander Orzechowski,Henning Urlaub,Juliane Liepe,Peter Lenart","doi":"10.1083/jcb.202312140","DOIUrl":"https://doi.org/10.1083/jcb.202312140","url":null,"abstract":"The Mos kinase activates the ERK/MAPK pathway during oocyte meiosis, controlling essential meiotic functions in species across metazoa. However, despite its significance, the molecular targets of Mos-MAPK remain largely unidentified. Here, we addressed this question using starfish oocytes ideally suited to combine cellular assays with phosphoproteomics. This revealed CPE-mediated mRNA polyadenylation as a prominent target of Mos-MAPK, and we show that translation is required to drive the second meiotic division. Secondly, we identify a well-defined subset of cytoskeletal regulators as targets of Mos-MAPK. We show that this regulation is critical to ensure the asymmetry of meiotic divisions, primarily by reducing the growth of astral microtubules. This allows positioning of the spindle directly beneath the cortex and prevents the separation of spindle poles in anaphase, thereby minimizing polar body size. Thus, by phosphoproteomics, we reveal molecular modules controlled by Mos-MAPK, explaining how this single, conserved kinase can act as a switch between the mitotic and meiotic division programs.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"14 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338699","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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