EMBO Reports最新文献_第8页

Rapid human oogonia-like cell specification via transcription factor-directed differentiation.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-23 DOI: 10.1038/s44319-025-00371-2

Merrick Pierson Smela, Christian C Kramme, Patrick R J Fortuna, Bennett Wolf, Shrey Goel, Jessica Adams, Carl Ma, Sergiy Velychko, Ursula Widocki, Venkata Srikar Kavirayuni, Tianlai Chen, Sophia Vincoff, Edward Dong, Richie E Kohman, Mutsumi Kobayashi, Toshi Shioda, George M Church, Pranam Chatterjee

{"title":"Rapid human oogonia-like cell specification via transcription factor-directed differentiation.","authors":"Merrick Pierson Smela, Christian C Kramme, Patrick R J Fortuna, Bennett Wolf, Shrey Goel, Jessica Adams, Carl Ma, Sergiy Velychko, Ursula Widocki, Venkata Srikar Kavirayuni, Tianlai Chen, Sophia Vincoff, Edward Dong, Richie E Kohman, Mutsumi Kobayashi, Toshi Shioda, George M Church, Pranam Chatterjee","doi":"10.1038/s44319-025-00371-2","DOIUrl":"10.1038/s44319-025-00371-2","url":null,"abstract":"The generation of germline cells from human induced pluripotent stem cells (hiPSCs) represents a milestone toward in vitro gametogenesis. Methods to recapitulate germline development beyond primordial germ cells in vitro have relied on long-term cell culture, such as 3-dimensional organoid co-culture for ~four months. Using a pipeline with highly parallelized screening, this study identifies combinations of TFs that directly and rapidly convert hiPSCs to induced oogonia-like cells (iOLCs). We demonstrate that co-expression of five TFs - namely, ZNF281, LHX8, SOHLH1, ZGLP1, and ANHX, induces high efficiency DDX4-positive iOLCs in only four days in a feeder-free monolayer culture condition. We also show improved production of human primordial germ cell-like cells (hPGCLCs) from hiPSCs by expression of DLX5, HHEX, and FIGLA. We characterize these TF-based iOLCs and hPGCLCs via gene and protein expression analyses and demonstrate their similarity to in vivo and in vitro-derived oogonia and primordial germ cells. Together, these results identify new regulatory factors that enhance human germ cell specification in vitro, and further establish unique computational and experimental tools for human in vitro oogenesis research.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1114-1143"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distinct mechanisms control the specific synaptic functions of Neuroligin 1 and Neuroligin 2. 不同的机制控制着神经胶质素1和神经胶质素2的特定突触功能。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44319-024-00286-4

Jinzhao Wang, Thomas Sudhof, Marius Wernig

{"title":"Distinct mechanisms control the specific synaptic functions of Neuroligin 1 and Neuroligin 2.","authors":"Jinzhao Wang, Thomas Sudhof, Marius Wernig","doi":"10.1038/s44319-024-00286-4","DOIUrl":"10.1038/s44319-024-00286-4","url":null,"abstract":"Neuroligins are postsynaptic cell-adhesion molecules that regulate synaptic function with a remarkable isoform specificity. Although Nlgn1 and Nlgn2 are highly homologous and biochemically interact with the same extra- and intracellular proteins, Nlgn1 selectively functions in excitatory synapses whereas Nlgn2 functions in inhibitory synapses. How this excitatory/inhibitory (E/I) specificity arises is unknown. Using a comprehensive structure-function analysis, we here expressed wild-type and mutant neuroligins in functional rescue experiments in cultured hippocampal neurons lacking all endogenous neuroligins. Electrophysiology confirmed that Nlgn1 and Nlgn2 selectively restored excitatory and inhibitory synaptic transmission, respectively, in neuroligin-deficient neurons, aligned with their synaptic localizations. Chimeric Nlgn1-Nlgn2 constructs reveal that the extracellular neuroligin domains confer synapse specificity, whereas their intracellular sequences are exchangeable. However, the cytoplasmic sequences of Nlgn2, including its Gephyrin-binding motif that is identically present in the Nlgn1, is essential for its synaptic function whereas they are dispensable for Nlgn1. These results demonstrate that although the excitatory vs. inhibitory synapse specificity of Nlgn1 and Nlgn2 are both determined by their extracellular sequences, these neuroligins enable normal synaptic connections via distinct intracellular mechanisms.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"860-879"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pro-inflammatory macrophage activation does not require inhibition of oxidative phosphorylation. 促炎巨噬细胞的激活不需要氧化磷酸化的抑制。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-03 DOI: 10.1038/s44319-024-00351-y

Andréa B Ball, Anthony E Jones, Kaitlyn B Nguyễn, Amy Rios, Nico Marx, Wei Yuan Hsieh, Krista Yang, Brandon R Desousa, Kristen K O Kim, Michaela Veliova, Zena Marie Del Mundo, Orian S Shirihai, Cristiane Benincá, Linsey Stiles, Steven J Bensinger, Ajit S Divakaruni

{"title":"Pro-inflammatory macrophage activation does not require inhibition of oxidative phosphorylation.","authors":"Andréa B Ball, Anthony E Jones, Kaitlyn B Nguyễn, Amy Rios, Nico Marx, Wei Yuan Hsieh, Krista Yang, Brandon R Desousa, Kristen K O Kim, Michaela Veliova, Zena Marie Del Mundo, Orian S Shirihai, Cristiane Benincá, Linsey Stiles, Steven J Bensinger, Ajit S Divakaruni","doi":"10.1038/s44319-024-00351-y","DOIUrl":"10.1038/s44319-024-00351-y","url":null,"abstract":"Pro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Oxidative phosphorylation sharply decreases upon classical macrophage activation, as mitochondria are thought to shift from ATP production towards accumulating signals that amplify effector function. However, evidence is conflicting regarding whether this collapse in respiration is essential or dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Different pro-inflammatory stimuli elicit varying effects on bioenergetic parameters, and pharmacologic and genetic models of electron transport chain inhibition show no causative link between respiration and macrophage activation. Furthermore, the signaling metabolites succinate and itaconate can accumulate independently of characteristic breaks in the TCA cycle in mouse and human macrophages, and peritoneal macrophages can be activated in vivo without inhibition of oxidative phosphorylation. The results indicate there is plasticity in the metabolic phenotypes that can support pro-inflammatory macrophage activation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"982-1002"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies. 精神分裂症相关的Xpo7单倍不足导致行为和核转运病理。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-07 DOI: 10.1038/s44319-024-00362-9

Saori Toyoda, Masataka Kikuchi, Yoshifumi Abe, Kyosei Tashiro, Takehisa Handa, Shingo Katayama, Yukiko Motokawa, Kenji F Tanaka, Hidehiko Takahashi, Hiroki Shiwaku

{"title":"Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies.","authors":"Saori Toyoda, Masataka Kikuchi, Yoshifumi Abe, Kyosei Tashiro, Takehisa Handa, Shingo Katayama, Yukiko Motokawa, Kenji F Tanaka, Hidehiko Takahashi, Hiroki Shiwaku","doi":"10.1038/s44319-024-00362-9","DOIUrl":"10.1038/s44319-024-00362-9","url":null,"abstract":"Recent genetic studies by the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) consortium have identified that protein-truncating variants of exportin 7 (XPO7) can increase the risk of schizophrenia (odds ratio, 28.1). Here we show that mice with Xpo7 haploinsufficiency (Xpo7+/- mice) present with cognitive and social behavioral impairments. Through proteome analysis using immunoprecipitation and frontal cortex nuclear isolation of Xpo7+/- mice, we identify 45 molecules interacting with Xpo7, including CutC, Rbfox3, and Gria3. Through single-nucleus RNA sequencing of the frontal cortex and striatum of Xpo7+/- mice differentiating between the onset and progressive stages, we also identify 284 gene expression changes that correlate with these stages. These genes encompass high-odds risk genes of schizophrenia identified by SCHEMA, including Gria3, Grin2A, Herc1, and Trio. Furthermore, our approach reveals 15 gene expression changes in the frontal cortex that correlate with the progressive stages. Our findings indicate the importance of investigating whether the interactions among the high-risk genes identified by SCHEMA contribute to a common schizophrenia pathology and underscore the significance of stage-dependent analysis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"948-981"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Male sex determination maintains proteostasis and extends lifespan of daf-18/PTEN deficient C. elegans. 雄性性别决定维持daf-18/PTEN缺陷秀丽隐杆线虫的蛋白质平衡并延长其寿命。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-16 DOI: 10.1038/s44319-025-00368-x

Zhi Qu, Lu Zhang, Xue Yin, Fangzhou Dai, Wei Huang, Yutong Zhang, Dongyang Ran, Shanqing Zheng

{"title":"Male sex determination maintains proteostasis and extends lifespan of daf-18/PTEN deficient C. elegans.","authors":"Zhi Qu, Lu Zhang, Xue Yin, Fangzhou Dai, Wei Huang, Yutong Zhang, Dongyang Ran, Shanqing Zheng","doi":"10.1038/s44319-025-00368-x","DOIUrl":"10.1038/s44319-025-00368-x","url":null,"abstract":"Although females typically have a survival advantage, those with PTEN functional abnormalities face a higher risk of developing tumors than males. However, the differences in how each sex responds to PTEN dysfunction have rarely been studied. We use Caenorhabditis elegans to investigate how male and hermaphrodite worms respond to dysfunction of the PTEN homolog daf-18. Our study reveals that male worms can counterbalance the negative effects of daf-18 deficiency, resulting in longer adult lifespan. The survival advantage depends on the loss of DAF-18 protein phosphatase activity, while its lipid phosphatase activity is dispensable. The deficiency in DAF-18 protein phosphatase activity leads to the failure of dephosphorylation of the endoplasmic reticulum membrane protein C18E9.2/SEC62, causing increased levels of unfolded and aggregated proteins in hermaphrodites. In contrast, males maintain proteostasis through a UNC-23/NEF-mediated protein ubiquitination and degradation process, providing them with a survival advantage. We find that sex determination is a key factor in regulating the differential expression of unc-23 between sexes in response to daf-18 loss. These findings highlight the unique role of the male sex determination pathway in regulating protein degradation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1084-1113"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The ingredients of a great scientific lecture.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-31 DOI: 10.1038/s44319-025-00382-z

David R Smith

引用次数: 0

CRISPR-Enabled Autonomous Transposable Element (CREATE) for RNA-based gene editing and delivery. CRISPR-Enabled Autonomous Transposable Element （CREATE）用于基于rna的基因编辑和传递。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-09 DOI: 10.1038/s44319-024-00364-7

Yuxiao Wang, Ruei-Zeng Lin, Meghan Harris, Bianca Lavayen, Neha Diwanji, Bruce McCreedy, Robert Hofmeister, Daniel Getts

{"title":"CRISPR-Enabled Autonomous Transposable Element (CREATE) for RNA-based gene editing and delivery.","authors":"Yuxiao Wang, Ruei-Zeng Lin, Meghan Harris, Bianca Lavayen, Neha Diwanji, Bruce McCreedy, Robert Hofmeister, Daniel Getts","doi":"10.1038/s44319-024-00364-7","DOIUrl":"10.1038/s44319-024-00364-7","url":null,"abstract":"To address a wide range of genetic diseases, genome editing tools that can achieve targeted delivery of large genes without causing double-strand breaks (DSBs) or requiring DNA templates are necessary. Here, we introduce CRISPR-Enabled Autonomous Transposable Element (CREATE), a genome editing system that combines the programmability and precision of CRISPR/Cas9 with the RNA-mediated gene insertion capabilities of the human LINE-1 (L1) element. CREATE employs a modified L1 mRNA to carry a payload gene, and a Cas9 nickase to facilitate targeted editing by L1-mediated reverse transcription and integration without relying on DSBs or DNA templates. Using this system, we demonstrate programmable insertion of a 1.1 kb gene expression cassette into specific genomic loci of human cell lines and primary T cells. Mechanistic studies reveal that CREATE editing is highly specific with no observed off-target events. Together, these findings establish CREATE as a programmable, RNA-based gene delivery technology with broad therapeutic potential.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1062-1083"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A phosphate-binding pocket in cyclin B3 is essential for XErp1/Emi2 degradation in meiosis I. 细胞周期蛋白B3中的磷酸盐结合袋对于减数分裂I中XErp1/Emi2的降解是必不可少的。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44319-024-00347-8

Rebecca Schunk, Marc Halder, Michael Schäfer, Elijah Johannes, Andreas Heim, Andreas Boland, Thomas U Mayer

{"title":"A phosphate-binding pocket in cyclin B3 is essential for XErp1/Emi2 degradation in meiosis I.","authors":"Rebecca Schunk, Marc Halder, Michael Schäfer, Elijah Johannes, Andreas Heim, Andreas Boland, Thomas U Mayer","doi":"10.1038/s44319-024-00347-8","DOIUrl":"10.1038/s44319-024-00347-8","url":null,"abstract":"To ensure the correct euploid state of embryos, it is essential that vertebrate oocytes await fertilization arrested at metaphase of meiosis II. This MII arrest is mediated by XErp1/Emi2, which inhibits the ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome). Cyclin B3 in complex with Cdk1 (cyclin-dependent kinase 1) is essential to prevent an untimely arrest of vertebrate oocytes in meiosis I by targeting XErp1/Emi2 for degradation. Yet, the molecular mechanism of XErp1/Emi2 degradation in MI is not well understood. Here, by combining TRIM-Away in oocytes with egg extract and in vitro studies, we demonstrate that a hitherto unknown phosphate-binding pocket in cyclin B3 is essential for efficient XErp1/Emi2 degradation in meiosis I. This pocket enables Cdk1/cyclin B3 to bind pre-phosphorylated XErp1/Emi2 facilitating further phosphorylation events, which ultimately target XErp1/Emi2 for degradation in a Plk1- (Polo-like kinase 1) dependent manner. Key elements of this degradative mechanism are conserved in frog and mouse. Our studies identify a novel, evolutionarily conserved determinant of Cdk/cyclin substrate specificity essential to prevent an untimely oocyte arrest at meiosis I with catastrophic consequences upon fertilization.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"768-790"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver. TRIM32通过控制肝脏中胰岛素受体的降解来调节胰岛素敏感性。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44319-024-00348-7

Shilpa Thakur, Priya Rawat, Budheswar Dehury, Prosenjit Mondal

{"title":"TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver.","authors":"Shilpa Thakur, Priya Rawat, Budheswar Dehury, Prosenjit Mondal","doi":"10.1038/s44319-024-00348-7","DOIUrl":"10.1038/s44319-024-00348-7","url":null,"abstract":"Impaired insulin receptor signaling is strongly linked to obesity-related metabolic conditions like non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes (T2DM). However, the exact mechanisms behind impaired insulin receptor (INSR) signaling in obesity induced by a high-fat diet remain elusive. In this study, we identify an E3 ubiquitin ligase, tripartite motif-containing protein 32 (TRIM32), as a key regulator of hepatic insulin signaling that targets the insulin receptor (INSR) for ubiquitination and proteasomal degradation in high-fat diet (HFD) mice. HFD induces the nuclear translocation of SREBP-1c (Sterol Regulatory Element-Binding Protein 1c), resulting in increased expression of TRIM32 in hepatocytes. TRIM32 ubiquitylates INSR and facilitates its proteasomal degradation, leading to severe insulin resistance and fat accumulation within the liver of high-fat diet induced obese (DIO) mice. Conversely, liver-specific knockdown of TRIM32 enhances INSR expression and hepatic insulin sensitivity. Reduced AMPK signaling and phosphorylation of SREBP-1c at S372 in high-fat DIO mice promotes the nuclear translocation of SREBP-1c, leading to increased TRIM32 expression. In conclusion, our results demonstrate that TRIM32 promotes diet-induced hepatic insulin resistance by targeting the INSR to degradation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"791-809"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author Correction: PP4 is a γH2AX phosphatase required for recovery from the DNA damage checkpoint. 作者更正：PP4 是一种从 DNA 损伤检查点恢复所需的γH2AX 磷酸酶。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 DOI: 10.1038/s44319-024-00338-9

Shinichiro Nakada, Ginny I Chen, Anne-Claude Gingras, Daniel Durocher

引用次数: 0