Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice
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...
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Elsevier
2025-06-01
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| Series: | European Journal of Cell Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171933525000056 |
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| author | Jorge Mata-Garrido Isabella Zafferri Alice Nordlinger Yann Loe-Mie Anne Dejean Jack-Christophe Cossec |
| author_facet | Jorge Mata-Garrido Isabella Zafferri Alice Nordlinger Yann Loe-Mie Anne Dejean Jack-Christophe Cossec |
| author_sort | Jorge Mata-Garrido |
| collection | DOAJ |
| description | 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 Fgfr 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. |
| format | Article |
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| institution | OA Journals |
| issn | 0171-9335 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| series | European Journal of Cell Biology |
| spelling | doaj-art-ab8ef1ce064942d3bbc18dbe7cce80972025-08-20T02:07:38ZengElsevierEuropean Journal of Cell Biology0171-93352025-06-01104215148010.1016/j.ejcb.2025.151480Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring miceJorge Mata-Garrido0Isabella Zafferri1Alice Nordlinger2Yann Loe-Mie3Anne Dejean4Jack-Christophe Cossec5Institut Pasteur, Université Paris Cité, Nuclear Organization and Oncogenesis Unit, Paris F-75015, France; INSERM, U993, Paris F-75015, France; Corresponding author at: Institut Pasteur, Université Paris Cité, Nuclear Organization and Oncogenesis Unit, Paris F-75015, France.Institut Pasteur, Université Paris Cité, Nuclear Organization and Oncogenesis Unit, Paris F-75015, France; INSERM, U993, Paris F-75015, FranceInstitut Pasteur, Université Paris Cité, Nuclear Organization and Oncogenesis Unit, Paris F-75015, France; INSERM, U993, Paris F-75015, FranceInstitut Pasteur, Université Paris Cité, Nuclear Organization and Oncogenesis Unit, Paris F-75015, France; INSERM, U993, Paris F-75015, France; Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics HUB, Paris F-75015, FranceInstitut Pasteur, Université Paris Cité, Nuclear Organization and Oncogenesis Unit, Paris F-75015, France; INSERM, U993, Paris F-75015, FranceInstitut Pasteur, Université Paris Cité, Nuclear Organization and Oncogenesis Unit, Paris F-75015, France; INSERM, U993, Paris F-75015, France; Corresponding author at: Institut Pasteur, Université Paris Cité, Nuclear Organization and Oncogenesis Unit, Paris F-75015, France.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 Fgfr 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.http://www.sciencedirect.com/science/article/pii/S0171933525000056Craniofacial syndromesSUMOylationEmbryonic developmentEpigeneticsCutis aplasiaUBA2-related syndrome |
| spellingShingle | Jorge Mata-Garrido Isabella Zafferri Alice Nordlinger Yann Loe-Mie Anne Dejean Jack-Christophe Cossec Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice European Journal of Cell Biology Craniofacial syndromes SUMOylation Embryonic development Epigenetics Cutis aplasia UBA2-related syndrome |
| title | Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice |
| title_full | Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice |
| title_fullStr | Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice |
| title_full_unstemmed | Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice |
| title_short | Transient pharmacological inhibition of SUMOylation during pregnancy induces craniofacial malformations in offspring mice |
| title_sort | transient pharmacological inhibition of sumoylation during pregnancy induces craniofacial malformations in offspring mice |
| topic | Craniofacial syndromes SUMOylation Embryonic development Epigenetics Cutis aplasia UBA2-related syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S0171933525000056 |
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