European journal of cell biology最新文献

{"title":"Galectin-8 drives ERK-dependent mitochondrial fragmentation, perinuclear relocation and mitophagy, with metabolic adaptations for cell proliferation","authors":"Adely de la Peña ,&nbsp;Claudio Retamal ,&nbsp;Francisca Pérez-Molina ,&nbsp;Nicole Díaz-Valdivia ,&nbsp;Francisco Veloso-Bahamondes ,&nbsp;Diego Tapia ,&nbsp;Jorge Cancino ,&nbsp;Felix Randow ,&nbsp;Alfonso González ,&nbsp;Claudia Oyanadel ,&nbsp;Andrea Soza","doi":"10.1016/j.ejcb.2025.151488","DOIUrl":"10.1016/j.ejcb.2025.151488","url":null,"abstract":"<div><div>Mitochondria adapt to the cell proliferative demands induced by growth factors through dynamic changes in morphology, distribution, and metabolic activity. Galectin-8 (Gal-8), a carbohydrate-binding protein that promotes cell proliferation by transactivating the EGFR-ERK signaling pathway, is overexpressed in several cancers. However, its impact on mitochondrial dynamics during cell proliferation remains unknown. Using MDCK and RPTEC kidney epithelial cells, we demonstrate that Gal-8 induces mitochondrial fragmentation and perinuclear redistribution. Additionally, mitochondria adopt donut-shaped morphologies, and live-cell imaging with two Keima-based reporters demonstrates Gal-8-induced mitophagy. ERK signaling inhibition abrogates all these Gal-8-induced mitochondrial changes and cell proliferation. Studies with established mutant versions of Gal-8 and CHO cells reveal that mitochondrial changes and proliferative response require interactions between the N-terminal carbohydrate recognition domain of Gal-8 and α-2,3-sialylated N-glycans at the cell surface. DRP1, a key regulator of mitochondrial fission, becomes phosphorylated in MDCK cells or overexpressed in RPTEC cells in an ERK-dependent manner, mediating mitochondrial fragmentation and perinuclear redistribution. Bafilomycin A abrogates Gal-8-induced cell proliferation, suggesting that mitophagy serves as an adaptation to cell proliferation demands. Functional analysis under Gal-8 stimulation shows that mitochondria maintain an active electron transport chain, partially uncoupled from ATP synthesis, and an increased membrane potential, indicative of healthy mitochondria. Meanwhile, the cells exhibit increased extracellular acidification rate and lactate production via aerobic glycolysis, a hallmark of an active proliferative state. Our findings integrate mitochondrial dynamics with metabolic adaptations during Gal-8-induced cell proliferation, with potential implications for physiology, disease, and therapeutic strategies.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151488"},"PeriodicalIF":4.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Versatility of vimentin assemblies: From filaments to biomolecular condensates and back","authors":"Dolores Pérez-Sala,&nbsp;Silvia Zorrilla","doi":"10.1016/j.ejcb.2025.151487","DOIUrl":"10.1016/j.ejcb.2025.151487","url":null,"abstract":"<div><div>Cytoskeletal structures shape and confer resistance to cells. The intermediate filament protein vimentin forms versatile structures that play key roles in cytoskeletal crosstalk, in the integration of cellular responses to a variety of external and internal cues, and in the defense against stress. Such multifaceted roles can be fulfilled thanks to the vast variety of vimentin proteoforms, which in turn arise from the combinations of a myriad of tightly regulated posttranslational modifications. Diverse vimentin proteoforms will differentially shape its polymeric assemblies, underlying vimentin ability to organize in filaments, bundles, squiggles, droplets, cell surface-bound and/or various secreted forms. Interestingly, certain vimentin dots or droplets have been lately categorized as biomolecular condensates. Biomolecular condensates are phase-separated membraneless structures that are critical for the organization of cellular components and play important roles in pathophysiology. Recent findings have unveiled the importance of low complexity sequence domains in vimentin filament assembly. Moreover, several oxidants trigger the transition of vimentin filaments into phase-separated biomolecular condensates, a reversible process that may provide clues on the role of condensates as seeds for filament formation. Revisiting previous results in the light of recent knowledge prompts the hypothesis that vimentin condensates could play a role in traffic of filament precursors, cytoskeletal crosstalk and cellular responses to stress. Deciphering the “vimentin posttranslational modification code”, that is, the structure-function relationships of vimentin proteoforms, constitutes a major challenge to understand the regulation of vimentin behavior and its multiple personalities. This will contribute to unveil essential cellular mechanisms and foster novel opportunities for drug discovery.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151487"},"PeriodicalIF":4.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human pluripotent stem cell-derived intestinal organoids for pharmacokinetic studies","authors":"Takumi Saito ,&nbsp;Junichiro Amako ,&nbsp;Teruhiko Watanabe ,&nbsp;Nobuaki Shiraki ,&nbsp;Shoen Kume","doi":"10.1016/j.ejcb.2025.151489","DOIUrl":"10.1016/j.ejcb.2025.151489","url":null,"abstract":"<div><div>The human small intestine is essential for orally administered drugs' absorption, metabolism, and excretion. Human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cells (IECs) offer a useful model for evaluating drug candidate compounds. We previously reported a protocol to generate matured enterocyte-like cells that exhibit P-gp-mediated efflux and cytochrome P450 3A (CYP3A)-mediated metabolism from human iPSCs. However, under the current protocols, generating iPSC-derived intestinal enterocyte-like cells requires a multi-step differentiation procedure and is time-consuming. Recent progress in intestinal organoid (IO) study provides an understanding of the growth factors that enable the maintenance of adult stem cells. Here, we established an easily accessible protocol using a direct 3D cluster culture to derive IOs from hiPSCs (iPSC-IOs) with high self-proliferative ability. The hiPSC-IOs can be propagated for a long-term and maintained capacity to differentiate and can be cryopreserved. Upon seeding on a two-dimensional monolayer, hiPSC-IOs gave rise to the intestinal epithelial cells (IECs) containing mature cell types of the intestine. The hiPSC-IOs-derived IECs contain enterocytes that show CYP metabolizing enzyme and transporter activities and can be used for pharmacokinetic studies.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151489"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activity and function of auxiliary fluxes of glucose metabolism in response to physiological normoxia (5 % O2) during long-term Adipose-Derived Stem/Stromal cell culture","authors":"Paulina Rybkowska ,&nbsp;Maria Kawalec ,&nbsp;Dorota Dymkowska ,&nbsp;Klaudia Radoszkiewicz ,&nbsp;Barbara Zabłocka ,&nbsp;Krzysztof Zabłocki ,&nbsp;Anna Sarnowska","doi":"10.1016/j.ejcb.2025.151486","DOIUrl":"10.1016/j.ejcb.2025.151486","url":null,"abstract":"<div><div>Energy metabolism homeostasis emerges as a dominant element influencing mesenchymal stem/stromal cells’ trajectory of development. The predominant glycolysis activity is a primary driver of cell proliferation and maintenance of the high-energetic state. Here, we examined the functions of two crucial auxiliary pathways: the phosphate-pentose pathway (PPP) and fructose-2,6-biphosphate pathway (FBP) to evaluate their impact on the therapeutic potential of Adipose-Derived Stem/Stromal cells (ASCs) during prolonged culture in various oxygen conditions: 5 % O₂ - physiological normoxia or 21 % O₂ - atmospheric oxygen. Our findings demonstrate that ASCs cultured in 5 % O₂ increased the rate of proliferation, migration, and expression of stemness factors, which is prominent during the initial and middle passages. Additionally, ASCs cultured in a 5 % O₂ exhibited heightened protection mechanisms against free radicals, increased LDH gene expression, and elevated extracellular acidification rate (ECAR). By estimating the HIF-1α level, we concluded that 5 % oxygen conditions were insufficient to induce a profound hypoxic state in ASCs. However, at the protein level, both the PPP and FBP pathways appeared to be more active in young (2-passage) cells, regardless of oxygen conditions, and their activity diminished over time. Additionally, the chemical suppression of G6PDH by Polydatin and inhibition of PFKFB3 by PFK-158 in ASCs (passage-2) revealed dose- and time-dependent effect on decreasing migratory capabilities of cells. Nevertheless, our work underscores the adaptable nature of ASC metabolism to prevailing external conditions, with the aging of the culture contributing to the decline in glycolysis-associated auxiliary pathways.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151486"},"PeriodicalIF":4.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in modeling the Charcot-Marie-Tooth disease: Human induced pluripotent stem cell-derived Schwann cells harboring SH3TC2 variants","authors":"Camille Loret ,&nbsp;Camille Scherrer ,&nbsp;Amandine Rovini ,&nbsp;Ioanna Pyromali ,&nbsp;Pierre-Antoine Faye ,&nbsp;Angélique Nizou ,&nbsp;Franck Sturtz ,&nbsp;Frédéric Favreau ,&nbsp;Anne-Sophie Lia","doi":"10.1016/j.ejcb.2025.151485","DOIUrl":"10.1016/j.ejcb.2025.151485","url":null,"abstract":"<div><div>Human induced pluripotent stem cells (hiPSCs) represent a powerful tool for investigating neuropathological disorders, such as Charcot-Marie-Tooth disease (CMT), the most prevalent inherited peripheral neuropathy, where the cells of interest are hardly accessible. Advancing the development of appropriate cellular models is crucial for studying the disease’s pathophysiology. In this study, we present the first two isogenic hiPSC-derived Schwann cell models for studying CMT4C, also known as AR-CMTde-<em>SH3TC2</em>. This subtype of CMT is associated with alterations in <em>SH3TC2</em> and is the most prevalent form of autosomal recessive demyelinating CMT. We aimed to study the impact of two nonsense mutations in <em>SH3TC2</em>. To achieve this, we used two CRISPR hiPSC clones, one carrying a homozygous nonsense mutation: c.211C&gt;T, p.Gln71*, and the other one, carrying the most common AR-CMTde-<em>SH3TC2</em> alteration, c.2860G&gt;A, p.Arg954*. To study the endogenous expression of SH3TC2 in the cells mainly altered in AR-CMTde-<em>SH3TC2</em>, we initiated the differentiation of both our CMT clones and their isogenic control into Schwann cells (SCs). This study represents the first <em>in vitro</em> investigation of human endogenous SH3TC2 expression in AR-CMTde-<em>SH3TC2</em> hiPSC-derived SC models, allowing for the examination of its expression and of its cellular impact. By comparing this AR-CMTde-<em>SH3TC2</em> models to the control one, we observed disparities in RNA and protein expression of SH3TC2. Additionally, our RNA and coculture experiments with hiPSC-derived motor neurons (MNs) revealed delayed maturation of SCs and a reduced ability of SH3TC2-deficient SCs to sustain motor neuron culture. Our findings also demonstrated a disability in receptor recycling in SH3TC2-deficient cells, depending on the AR-CMTde-<em>SH3TC2</em> alteration. These hiPSC-derived-SC models further provide a new modelling tool for studying Schwann cell contribution to CMT4C.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151485"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau","authors":"Keiko Imamura ,&nbsp;Ayako Nagahashi ,&nbsp;Aya Okusa ,&nbsp;Tomoki Sakasai ,&nbsp;Kayoko Tsukita ,&nbsp;Yumiko Kutoku ,&nbsp;Yutaka Ohsawa ,&nbsp;Yoshihide Sunada ,&nbsp;Naruhiko Sahara ,&nbsp;Nicholas M. Kanaan ,&nbsp;Makoto Higuchi ,&nbsp;Kohji Mori ,&nbsp;Manabu Ikeda ,&nbsp;Haruhisa Inoue","doi":"10.1016/j.ejcb.2025.151484","DOIUrl":"10.1016/j.ejcb.2025.151484","url":null,"abstract":"<div><div>Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify disease-modifying treatments, we conducted drug screening using neurons derived from induced pluripotent stem cells (iPSCs) of FTLD-Tau patients. This screening identified gabapentin as an existing drug that suppresses neuronal cell death with suppressed accumulation of Tau oligomers. Treatment with gabapentinoids, including pregabalin and mirogabalin, demonstrated similar neuroprotective effects. These compounds bind to the α2δ subunit of voltage-dependent calcium channels and specifically target the two isoforms α2δ-1 and α2δ-2. To determine which isoform is involved in the neurodegeneration seen in FTLD-Tau, we employed a knockout approach using iPSCs, which revealed that α2δ-2, encoded by CACNA2D2, plays a key role in the degeneration of FTLD-Tau neurons. Moreover, Neural organoids of FTLD-Tau exhibited features indicative of neurodegeneration, and CACNA2D2 knockout reversed a part of the gene expression alterations associated with these neurodegenerative features. These findings suggest that α2δ-2 may be a promising target for disease-modifying therapies in FTLD-Tau.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151484"},"PeriodicalIF":4.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of prostanoids in regulatory T cells and their implications in inflammatory diseases and cancers","authors":"Somsak Prasongtanakij ,&nbsp;Kitipong Soontrapa ,&nbsp;Dean Thumkeo","doi":"10.1016/j.ejcb.2025.151482","DOIUrl":"10.1016/j.ejcb.2025.151482","url":null,"abstract":"<div><div>Regulatory T cells (Tregs) play an important role in the immune system through the regulation of immunological self-tolerance and homeostasis. Furthermore, increasing evidence suggests the potential contribution of Tregs beyond immunity in the process of repairing various injured tissues. Tregs are generally characterised by the constitutive expression of forkhead box protein 3 (FOXP3) transcription factor in the nucleus and high expression levels of CD25 and CTLA-4 on the cell surface. To date, a large number of molecules have been identified as key regulators of Treg differentiation and function. Among these molecules are prostanoids, which are multifaceted lipid mediators. Prostanoids are produced from arachidonic acid through the catalytic activity of the enzyme cyclooxygenase and exert their functions through the 9 cognate receptors, DP1‐2, EP1-EP4, FP, IP and TP. We briefly review previous studies on the regulatory mechanism of Tregs and then discuss recent works on the modulatory role of prostanoids.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151482"},"PeriodicalIF":4.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dual nature of KLHL proteins: From cellular regulators to disease drivers","authors":"Verdiana Di Giulio ,&nbsp;Angelo Canciello ,&nbsp;Erminia Carletti ,&nbsp;Antonella De Luca ,&nbsp;Antonio Giordano ,&nbsp;Andrea Morrione ,&nbsp;Jacopo Berardinelli ,&nbsp;Valentina Russo ,&nbsp;Domenico Solari ,&nbsp;Luigi Maria Cavallo ,&nbsp;Barbara Barboni","doi":"10.1016/j.ejcb.2025.151483","DOIUrl":"10.1016/j.ejcb.2025.151483","url":null,"abstract":"<div><div>The Kelch-like (KLHL) protein family, characterized by its conserved BTB, BACK, and Kelch domains, serves as substrate adaptors for Cullin 3-RING ligases (CRL3), facilitating the ubiquitination and degradation of specific target proteins. Through this mechanism, KLHL proteins regulate numerous physiological processes, including cytoskeletal organization, oxidative stress response, and cell cycle progression. Dysregulation of KLHL proteins—via mutations or abnormal expression—has been implicated in various pathological conditions, including neurodegenerative disorders, cancer, cardiovascular diseases, and hereditary syndromes. This review provides a comprehensive overview of the physiological and pathological roles of KLHL proteins, emphasizing their specific substrates and mechanisms of action. By integrating structural and mechanistic insights with translational research, this review underscores the potential of KLHL proteins as promising therapeutic targets, offering new opportunities to combat a wide spectrum of complex diseases.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151483"},"PeriodicalIF":4.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of organoid genetics","authors":"Thomas M. Klompstra ,&nbsp;Ki-Jun Yoon ,&nbsp;Bon-Kyoung Koo","doi":"10.1016/j.ejcb.2025.151481","DOIUrl":"10.1016/j.ejcb.2025.151481","url":null,"abstract":"<div><div>Organoids have revolutionized <em>in vitro</em> research by offering three-dimensional, multicellular systems that recapitulate the structure, function, and genetics of human tissues. Initially developed from both pluripotent stem cells (PSCs) and adult stem cells (AdSCs), organoids have expanded to model nearly every major human organ, significantly advancing developmental biology, disease modeling, and therapeutic screening. This review highlights the progression of organoid technologies, emphasizing the integration of genetic tools, including CRISPR-Cas9, prime editing, and lineage tracing. These advancements have facilitated precise modeling of human-specific pathologies and drug responses, often surpassing traditional 2D cultures and animal models in accuracy. Emerging technologies, such as organoid fusion, xenografting, and optogenetics, are expected to further enhance our understanding of cellular interactions and microenvironmental dynamics. As organoid complexity and genetic engineering methods continue to evolve, they will become increasingly indispensable for personalized medicine and translational research, bridging gaps between <em>in vitro</em> and <em>in vivo</em> systems.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151481"},"PeriodicalIF":4.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice","authors":"Jorge Mata-Garrido ,&nbsp;Isabella Zafferri ,&nbsp;Alice Nordlinger ,&nbsp;Yann Loe-Mie ,&nbsp;Anne Dejean ,&nbsp;Jack-Christophe Cossec","doi":"10.1016/j.ejcb.2025.151480","DOIUrl":"10.1016/j.ejcb.2025.151480","url":null,"abstract":"<div><div>Cell identity plays a pivotal role in embryo development, guiding the process of cellular differentiation essential for tissue and organ formation. Post-translational modification by the ubiquitin-related SUMO protein acts as a chromatin barrier to cell fate conversions. While SUMOylation deficiency is incompatible with mammalian embryonic development, haploinsufficiency for the SUMOylation machinery's E1 enzyme, UBA2, leads to various phenotypic traits in humans, including craniofacial malformations and aplasia cutis congenita. To investigate SUMO's role in organogenesis, SUMOylation was transiently suppressed using a specific pharmacological inhibitor, TAK981, administered during the early post-implantation embryo stage. A high-concentration injection led to embryonic lethality associated with epigenetic scars and alterations in nuclear and nucleolar integrity observed in treated embryo-derived fibroblasts. Lower-concentration injections resulted in viable mice with craniofacial deformities often accompanied by hydrocephalus, syndactyly and an aplasia cutis-like phenotype. Transcriptomic analysis revealed the repression of genes involved in neural crest differentiation in the TAK981-treated embryos as well as the overexpression of the <em>Fgfr</em> gene family in the adult TAK981 progeny. These genes, expressed in neural crest derivatives, are known for their gain-of-function mutations linked to human craniosynostosis syndromes, suggesting that potential overactivation of the FGF signaling pathway may contribute to the malformations observed in TAK981 progeny. Altogether, disruption of the SUMOylation/deSUMOylation equilibrium during a short embryonic period is sufficient to induce persistent cellular defects and transcriptional alterations, resulting in severe offspring malformations. In conclusion, the SUMO inhibitor TAK981 has teratogenic effects, disrupting normal fetal development and causing congenital disabilities reminiscent of traits observed in UBA2-related syndrome.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151480"},"PeriodicalIF":4.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}