TMC1, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. TMC1 codes for the transmembrane channel-like protein 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca2+ regulation in MET remains unclear. Calcium and integrin-binding protein 2 (CIB2), another MET component associated with deafness, can bind with Ca2+. Our study shows that TMC1-CIB2 complex undergoes a Ca2+-induced conformational change. We identified a vertebrate-specific binding site on TMC1 that interacts with apo CIB2, linked with hearing loss. Using an ex vivo mouse organotypic cochlea model, we demonstrated that disruption of the calcium-binding site of CIB2 perturbs the MET channel conductivity. After systematically analyzing the hearing loss variants, we observed dominant mutations of TMC1 cluster around the putative ion pore or at the binding interfaces with CIB2. These findings elucidate the molecular mechanisms underlying TMC1-linked hearing loss.
{"title":"Mechano-electrical transduction components TMC1-CIB2 undergo a Ca2+-induced conformational change linked to hearing loss","authors":"Shaoxuan Wu, Lin Lin, Qiaoyu Hu, Xuebo Yao, Hongyang Wang, Shuang Liu, Qingling Liu, Yuehui Xi, Yuzhe Lin, Jianqiao Gong, Ruixing Hu, Wei Zhan, Yi Luo, Guang He, Zhijun Liu, Wei Xiong, Qiuju Wang, Zhigang Xu, Fang Bai, Qing Lu","doi":"10.1016/j.devcel.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.004","url":null,"abstract":"<em>TMC1</em>, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. <em>TMC1</em> codes for the transmembrane channel-like protein 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca<sup>2+</sup> regulation in MET remains unclear. Calcium and integrin-binding protein 2 (CIB2), another MET component associated with deafness, can bind with Ca<sup>2+</sup>. Our study shows that TMC1-CIB2 complex undergoes a Ca<sup>2+</sup>-induced conformational change. We identified a vertebrate-specific binding site on TMC1 that interacts with <em>apo</em> CIB2, linked with hearing loss. Using an <em>ex vivo</em> mouse organotypic cochlea model, we demonstrated that disruption of the calcium-binding site of CIB2 perturbs the MET channel conductivity. After systematically analyzing the hearing loss variants, we observed dominant mutations of TMC1 cluster around the putative ion pore or at the binding interfaces with CIB2. These findings elucidate the molecular mechanisms underlying <em>TMC1</em>-linked hearing loss.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"40 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056429","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 : 2025-01-24DOI: 10.1016/j.devcel.2025.01.001
Jerry J. Fan, Anders W. Erickson, Julia Carrillo-Garcia, Xin Wang, Patryk Skowron, Xian Wang, Xin Chen, Guanqiao Shan, Wenkun Dou, Shahrzad Bahrampour, Yi Xiong, Weifan Dong, Namal Abeysundara, Michelle A. Francisco, Ronwell J. Pusong, Wei Wang, Miranda Li, Elliot Ying, Raúl A. Suárez, Hamza Farooq, Xi Huang
Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo and applied this to sonic hedgehog (SHH) medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver. KCNB2 governs cell volume of MB-propagating cells (MPCs), with KCNB2 depletion causing osmotic swelling, decreased plasma membrane tension, and elevated endocytic internalization of epidermal growth factor receptor (EGFR), thereby mitigating proliferation of MPCs to ultimately impair MB growth. KCNB2 is largely dispensable for mouse development and KCNB2 knockout synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance drivers and elucidate a mechanism by which potassium homeostasis integrates biomechanical and biochemical signaling to promote MB aggression.
{"title":"A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance","authors":"Jerry J. Fan, Anders W. Erickson, Julia Carrillo-Garcia, Xin Wang, Patryk Skowron, Xian Wang, Xin Chen, Guanqiao Shan, Wenkun Dou, Shahrzad Bahrampour, Yi Xiong, Weifan Dong, Namal Abeysundara, Michelle A. Francisco, Ronwell J. Pusong, Wei Wang, Miranda Li, Elliot Ying, Raúl A. Suárez, Hamza Farooq, Xi Huang","doi":"10.1016/j.devcel.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.001","url":null,"abstract":"Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes <em>in vivo</em> and applied this to sonic hedgehog (SHH) medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel <em>KCNB2</em> as a candidate maintenance driver. KCNB2 governs cell volume of MB-propagating cells (MPCs), with KCNB2 depletion causing osmotic swelling, decreased plasma membrane tension, and elevated endocytic internalization of epidermal growth factor receptor (EGFR), thereby mitigating proliferation of MPCs to ultimately impair MB growth. KCNB2 is largely dispensable for mouse development and KCNB2 knockout synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance drivers and elucidate a mechanism by which potassium homeostasis integrates biomechanical and biochemical signaling to promote MB aggression.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"52 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026719","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 : 2025-01-24DOI: 10.1016/j.devcel.2025.01.002
Filip Vasilev, Aleksandar I. Mihajlović, Gaudeline Rémillard-Labrosse, Greg FitzHarris
Apoptosis is a key feature of preimplantation development, but whether it occurs in a cell-autonomous or coordinated manner was unknown. Here, we report that plasma membrane abscission, the final step of cell division, is profoundly delayed in early mouse embryos such that a cytokinetic bridge is maintained for the vast majority of the following interphase. Early embryos thus consist of many pairs of sister cells connected by stable cytokinetic bridges that allow them to share diffusible molecules. We show that apoptotic regulators are shared through cytokinetic bridges and that these bridges ensure that if one cell enters apoptosis, its sister cell does as well. Long-lived cytokinetic bridges are thus a previously unappreciated form of cell-cell communication within the mouse embryo that coordinate the clearance of pairs of cells with similar developmental histories.
{"title":"Long-lived cytokinetic bridges coordinate sister-cell elimination in mouse embryos","authors":"Filip Vasilev, Aleksandar I. Mihajlović, Gaudeline Rémillard-Labrosse, Greg FitzHarris","doi":"10.1016/j.devcel.2025.01.002","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.002","url":null,"abstract":"Apoptosis is a key feature of preimplantation development, but whether it occurs in a cell-autonomous or coordinated manner was unknown. Here, we report that plasma membrane abscission, the final step of cell division, is profoundly delayed in early mouse embryos such that a cytokinetic bridge is maintained for the vast majority of the following interphase. Early embryos thus consist of many pairs of sister cells connected by stable cytokinetic bridges that allow them to share diffusible molecules. We show that apoptotic regulators are shared through cytokinetic bridges and that these bridges ensure that if one cell enters apoptosis, its sister cell does as well. Long-lived cytokinetic bridges are thus a previously unappreciated form of cell-cell communication within the mouse embryo that coordinate the clearance of pairs of cells with similar developmental histories.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"2 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026716","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 : 2025-01-21DOI: 10.1016/j.devcel.2025.01.006
Biruk A. Feyissa, Elsa M. de Becker, Coralie E. Salesse-Smith, Mengjun Shu, Jin Zhang, Timothy B. Yates, Meng Xie, Kuntal De, Dhananjay Gotarkar, Margot S.S. Chen, Sara S. Jawdy, Dana L. Carper, Kerrie Barry, Jeremy Schmutz, David J. Weston, Paul E. Abraham, Chung-Jui Tsai, Jennifer L. Morrell-Falvey, Gail Taylor, Jin-Gui Chen, Wellington Muchero
(Developmental Cell 60, 1–12.e1–e7; March 10, 2025)
(发育细胞60,1-12.e1-e7；2025年3月10日)
{"title":"An orphan gene BOOSTER enhances photosynthetic efficiency and plant productivity","authors":"Biruk A. Feyissa, Elsa M. de Becker, Coralie E. Salesse-Smith, Mengjun Shu, Jin Zhang, Timothy B. Yates, Meng Xie, Kuntal De, Dhananjay Gotarkar, Margot S.S. Chen, Sara S. Jawdy, Dana L. Carper, Kerrie Barry, Jeremy Schmutz, David J. Weston, Paul E. Abraham, Chung-Jui Tsai, Jennifer L. Morrell-Falvey, Gail Taylor, Jin-Gui Chen, Wellington Muchero","doi":"10.1016/j.devcel.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.01.006","url":null,"abstract":"(Developmental Cell <em>60</em>, 1–12.e1–e7; March 10, 2025)","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"28 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990652","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 : 2025-01-20DOI: 10.1016/j.devcel.2024.12.018
Frederick J.H. Whiting, Trevor A. Graham
Genetic mutations cause colorectal cancer (CRC) initiation, but their contribution to metastasis and therapy resistance is less clear. In a recent issue of Nature, Moorman et al.1 use single-cell transcriptome sequencing to map the changes in cancer cell state (cell phenotypes) that occur through CRC progression.
{"title":"Plasticity in metastatic colorectal cancer","authors":"Frederick J.H. Whiting, Trevor A. Graham","doi":"10.1016/j.devcel.2024.12.018","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.018","url":null,"abstract":"Genetic mutations cause colorectal cancer (CRC) initiation, but their contribution to metastasis and therapy resistance is less clear. In a recent issue of <em>Nature</em>, Moorman et al.<span><span><sup>1</sup></span></span> use single-cell transcriptome sequencing to map the changes in cancer cell state (cell phenotypes) that occur through CRC progression.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"122 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990086","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 : 2025-01-16DOI: 10.1016/j.devcel.2024.12.039
Gordana Scepanovic, Negar Balaghi, Katheryn E. Rothenberg, Rodrigo Fernandez-Gonzalez
Embryonic wounds repair rapidly, with no inflammation or scarring. Embryonic wound healing is driven by collective cell movements facilitated by the increase in the volume of the cells adjacent to the wound. The mechanistic target of rapamycin (mTor) complex 1 (TORC1) is associated with cell growth. We found that disrupting TORC1 signaling in Drosophila embryos prevented cell volume increases and slowed down wound repair. Catabolic processes, such as autophagy, can inhibit cell growth. Five-dimensional microscopy demonstrated that the number of autophagosomes decreased during wound repair, suggesting that autophagy must be tightly regulated for rapid wound healing. mTor inhibition increased autophagy, and activating autophagy prevented cell volume expansion and slowed down wound closure. Finally, reducing autophagy in embryos with disrupted TORC1 signaling rescued cell volume changes and rapid wound repair. Together, our results show that TORC1 activation upon wounding negatively regulates autophagy, allowing cells to increase their volumes to facilitate rapid wound healing.
{"title":"mTor limits autophagy to facilitate cell volume expansion and rapid wound repair in Drosophila embryos","authors":"Gordana Scepanovic, Negar Balaghi, Katheryn E. Rothenberg, Rodrigo Fernandez-Gonzalez","doi":"10.1016/j.devcel.2024.12.039","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.039","url":null,"abstract":"Embryonic wounds repair rapidly, with no inflammation or scarring. Embryonic wound healing is driven by collective cell movements facilitated by the increase in the volume of the cells adjacent to the wound. The mechanistic target of rapamycin (mTor) complex 1 (TORC1) is associated with cell growth. We found that disrupting TORC1 signaling in <em>Drosophila</em> embryos prevented cell volume increases and slowed down wound repair. Catabolic processes, such as autophagy, can inhibit cell growth. Five-dimensional microscopy demonstrated that the number of autophagosomes decreased during wound repair, suggesting that autophagy must be tightly regulated for rapid wound healing. mTor inhibition increased autophagy, and activating autophagy prevented cell volume expansion and slowed down wound closure. Finally, reducing autophagy in embryos with disrupted TORC1 signaling rescued cell volume changes and rapid wound repair. Together, our results show that TORC1 activation upon wounding negatively regulates autophagy, allowing cells to increase their volumes to facilitate rapid wound healing.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"38 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987025","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 : 2025-01-15DOI: 10.1016/j.devcel.2024.12.038
Madalena M. Reimão-Pinto, Sebastian M. Castillo-Hair, Georg Seelig, Alexander F. Schier
The 5′ UTRs of mRNAs are critical for translation regulation during development, but their in vivo regulatory features are poorly characterized. Here, we report the regulatory landscape of 5′ UTRs during early zebrafish embryogenesis using a massively parallel reporter assay of 18,154 sequences coupled to polysome profiling. We found that the 5′ UTR suffices to confer temporal dynamics to translation initiation and identified 86 motifs enriched in 5′ UTRs with distinct ribosome recruitment capabilities. A quantitative deep learning model, Danio Optimus 5-Prime (DaniO5P), identified a combined role for 5′ UTR length, translation initiation site context, upstream AUGs, and sequence motifs on ribosome recruitment. DaniO5P predicts the activities of maternal and zygotic 5′ UTR isoforms and indicates that modulating 5′ UTR length and motif grammar contributes to translation initiation dynamics. This study provides a first quantitative model of 5′ UTR-based translation regulation in development and lays the foundation for identifying the underlying molecular effectors.
{"title":"The regulatory landscape of 5′ UTRs in translational control during zebrafish embryogenesis","authors":"Madalena M. Reimão-Pinto, Sebastian M. Castillo-Hair, Georg Seelig, Alexander F. Schier","doi":"10.1016/j.devcel.2024.12.038","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.038","url":null,"abstract":"The 5′ UTRs of mRNAs are critical for translation regulation during development, but their <em>in vivo</em> regulatory features are poorly characterized. Here, we report the regulatory landscape of 5′ UTRs during early zebrafish embryogenesis using a massively parallel reporter assay of 18,154 sequences coupled to polysome profiling. We found that the 5′ UTR suffices to confer temporal dynamics to translation initiation and identified 86 motifs enriched in 5′ UTRs with distinct ribosome recruitment capabilities. A quantitative deep learning model, <em>Danio</em> Optimus 5-Prime (DaniO5P), identified a combined role for 5′ UTR length, translation initiation site context, upstream AUGs, and sequence motifs on ribosome recruitment. DaniO5P predicts the activities of maternal and zygotic 5′ UTR isoforms and indicates that modulating 5′ UTR length and motif grammar contributes to translation initiation dynamics. This study provides a first quantitative model of 5′ UTR-based translation regulation in development and lays the foundation for identifying the underlying molecular effectors.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"49 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981360","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 : 2025-01-14DOI: 10.1016/j.devcel.2024.12.036
Qingzhong Li, Tao Hu, Tianjiao Lu, Bo Yu, Yang Zhao
Drought and salinity are significant environmental threats that cause hyperosmotic stress in plants, which respond with a transient elevation of cytosolic Ca2+ and activation of Snf1-related protein kinase 2s (SnRK2s) and downstream responses. The exact regulators decoding Ca2+ signals to activate downstream responses remained unclear. Here, we show that the calcium-dependent protein kinases CPK3/4/6/11 and 27 respond to moderate osmotic stress and dehydration to activate SnRK2 phosphorylation in Arabidopsis. Using quantitative phosphoproteomics in a higher-order mutant lacking 12 pyrabactin resistance 1-like (PYL) abscisic acid (ABA) receptors, we identified six CPKs that are phosphorylated under osmotic stress. CPK3/4/6/11/27 phosphorylate the SnRK2s on multiple phosphosites within the activation loop. The cpk3/4/6/11/27 mutant is defective in SnRK2 activation, seed germination, and seedling growth under mild osmotic stress. Our findings elucidate the critical roles of CPK3/4/6/11/27 in decoding Ca2+ signals to activate SnRK2s and demonstrate a CPK-SnRK2 kinase cascade controlling osmotic stress responses in plants.
{"title":"Calcium-dependent protein kinases CPK3/4/6/11 and 27 respond to osmotic stress and activate SnRK2s in Arabidopsis","authors":"Qingzhong Li, Tao Hu, Tianjiao Lu, Bo Yu, Yang Zhao","doi":"10.1016/j.devcel.2024.12.036","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.036","url":null,"abstract":"Drought and salinity are significant environmental threats that cause hyperosmotic stress in plants, which respond with a transient elevation of cytosolic Ca<sup>2+</sup> and activation of Snf1-related protein kinase 2s (SnRK2s) and downstream responses. The exact regulators decoding Ca<sup>2+</sup> signals to activate downstream responses remained unclear. Here, we show that the calcium-dependent protein kinases CPK3/4/6/11 and 27 respond to moderate osmotic stress and dehydration to activate SnRK2 phosphorylation in <em>Arabidopsis</em>. Using quantitative phosphoproteomics in a higher-order mutant lacking 12 <em>pyrabactin resistance 1-like</em> (<em>PYL</em>) abscisic acid (ABA) receptors, we identified six CPKs that are phosphorylated under osmotic stress. CPK3/4/6/11/27 phosphorylate the SnRK2s on multiple phosphosites within the activation loop. The <em>cpk3/4/6/11/27</em> mutant is defective in SnRK2 activation, seed germination, and seedling growth under mild osmotic stress. Our findings elucidate the critical roles of CPK3/4/6/11/27 in decoding Ca<sup>2+</sup> signals to activate SnRK2s and demonstrate a CPK-SnRK2 kinase cascade controlling osmotic stress responses in plants.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"51 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974564","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 : 2025-01-14DOI: 10.1016/j.devcel.2024.12.037
Stephanie Gehrs, Moritz Jakab, Ewgenija Gutjahr, Zuguang Gu, Dieter Weichenhan, Jan-Philipp Mallm, Carolin Mogler, Matthias Schlesner, Christoph Plass, Katharina Schlereth, Hellmut G. Augustin
The labyrinthian fetoplacental capillary network is vital for proper nourishment of the developing embryo. Dysfunction of the maternal-fetal circulation is a primary cause of placental insufficiency. Here, we show that the spatial zonation of the murine placental labyrinth vasculature is controlled by flow-regulated epigenetic mechanisms. Spatiotemporal transcriptomic profiling identified a gradual change in the expression of epigenetic enzymes, including the de novo DNA methyltransferase 3a (DNMT3A). Loss of Dnmt3a resulted in DNA hypomethylation and perturbation of zonated placental gene expression. The resulting global DNA hypomethylation impaired the angiogenic capacity of endothelial cells. Global or endothelium-predominant deletion of Dnmt3a resulted in impaired placental vascularization and fetal growth retardation (FGR). Human placental endothelial gene expression profiling associated preeclampsia with reduced DNMT3A expression. Collectively, our study identified DMNT3A as critical methylome-regulator of placental endothelial gene expression and function with clinical implications for placental dysfunction, as it occurs during preeclampsia or FGR.
{"title":"The spatial zonation of the murine placental vasculature is specified by epigenetic mechanisms","authors":"Stephanie Gehrs, Moritz Jakab, Ewgenija Gutjahr, Zuguang Gu, Dieter Weichenhan, Jan-Philipp Mallm, Carolin Mogler, Matthias Schlesner, Christoph Plass, Katharina Schlereth, Hellmut G. Augustin","doi":"10.1016/j.devcel.2024.12.037","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.12.037","url":null,"abstract":"The labyrinthian fetoplacental capillary network is vital for proper nourishment of the developing embryo. Dysfunction of the maternal-fetal circulation is a primary cause of placental insufficiency. Here, we show that the spatial zonation of the murine placental labyrinth vasculature is controlled by flow-regulated epigenetic mechanisms. Spatiotemporal transcriptomic profiling identified a gradual change in the expression of epigenetic enzymes, including the <em>de novo</em> DNA methyltransferase 3a (DNMT3A). Loss of <em>Dnmt3a</em> resulted in DNA hypomethylation and perturbation of zonated placental gene expression. The resulting global DNA hypomethylation impaired the angiogenic capacity of endothelial cells. Global or endothelium-predominant deletion of <em>Dnmt3a</em> resulted in impaired placental vascularization and fetal growth retardation (FGR). Human placental endothelial gene expression profiling associated preeclampsia with reduced DNMT3A expression. Collectively, our study identified DMNT3A as critical methylome-regulator of placental endothelial gene expression and function with clinical implications for placental dysfunction, as it occurs during preeclampsia or FGR.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"22 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974567","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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