The FASEB Journal最新文献

{"title":"DHFR2 RNA directly regulates dihydrofolate reductase and its expression level impacts folate one carbon metabolism","authors":"Paola Drago,&nbsp;Niamh Bookey,&nbsp;Kit-Yi Leung,&nbsp;Michael Henry,&nbsp;Paula Meleady,&nbsp;Nicholas D. E. Greene,&nbsp;Anne Parle-McDermott","doi":"10.1096/fj.202401039RR","DOIUrl":"https://doi.org/10.1096/fj.202401039RR","url":null,"abstract":"<p>Dihydrofolate reductase activity is required in One Carbon Metabolism to ensure that the biologically active form of folate, tetrahydrofolate, is replenished and available as an enzyme cofactor for numerous cellular reactions, including purine and pyrimidine synthesis. Most cellular enzyme activity was thought to arise from the product of the <i>DHFR</i> gene on chromosome 5, with its paralogue <i>DHFR2</i> (formerly known as DHFRL1; [chromosome 3]), believed to be responsible for mitochondrial dihydrofolate activity based on recombinant versions of the enzyme. In this paper, we confirm our earlier findings that dihydrofolate reductase activity in mitochondria is derived from the <i>DHFR</i> gene rather than <i>DHFR2</i> and that endogenous DHFR2 protein is not detectable in most cells and tissues. Using HepG2 cell lines with modulated expression of either DHFR or DHFR2, we observed an impact of <i>DHFR2</i> RNA on One Carbon Metabolism mediated through an influence on DHFR expression and activity. Knockout of <i>DHFR2</i> results in a drop in dihydrofolate reductase activity, lowered 10-formyltetrahydrofolate abundance, downregulation of <i>DHFR</i> mRNA, and diminished DHFR protein abundance. We also observed downregulation of Serine Hydroxymethyltransferase and Thymidylate Synthase, two One Carbon Metabolism enzymes that work with DHFR to support de novo thymidylate synthesis. The expression of recombinant DHFR2 resulted in restoration of DHFR mRNA and protein levels while a DHFR knockdown cell line showed upregulation of DHFR2 RNA. We propose that the <i>DHFR2</i> gene encodes an RNA molecule that regulates cellular dihydrofolate reductase activity through its impact on DHFR mRNA and protein.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401039RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NUP98-p65 complex regulates DNA repair to maintain glioblastoma stem cells","authors":"Feifei Li,&nbsp;Ying Zhang,&nbsp;Jiahui Li,&nbsp;Ranran Jiang,&nbsp;Shusheng Ci","doi":"10.1096/fj.202403256R","DOIUrl":"https://doi.org/10.1096/fj.202403256R","url":null,"abstract":"<p>The nuclear pore complex (NPC) is an evolutionarily conserved structure that maintains the traffic between the nucleus and cytoplasm. Here, we profiled the expression of nucleoporins (NUPs) in glioblastoma stem cells (GSCs) and found that NUP98 promoted GSC maintenance and therapeutic resistance. GSCs preferentially expressed NUP98, which is essential for GSC tumorigenesis in vitro and in vivo. RNA sequencing demonstrated that NUP98 regulated the expression of key DNA damage and repair pathways. NUP98 formed a complex with transcription factor p65 to directly activate genes involved in homologous repair. Attenuation of NUP98 or p65 expression induced unrepaired intrinsic DNA damage and sensitized GSC to ionizing radiation. Clinically, overexpression of NUP98 informs poor clinical outcome among glioblastoma (GBM) patients. Collectively, our results demonstrate that NUP98-p65 represents a novel node in the regulation of DNA repair, suggesting a therapeutic strategy with potential clinical benefits for GBM patients.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iPSC-derived human cortical organoids display profound alterations of cellular homeostasis following SARS-CoV-2 infection and Spike protein exposure","authors":"Gioia Cappelletti,&nbsp;Lorenzo Brambilla,&nbsp;Sergio Strizzi,&nbsp;Fiona Limanaqi,&nbsp;Valentina Melzi,&nbsp;Mafalda Rizzuti,&nbsp;Monica Nizzardo,&nbsp;Irma Saulle,&nbsp;Daria Trabattoni,&nbsp;Stefania Corti,&nbsp;Mario Clerici,&nbsp;Mara Biasin","doi":"10.1096/fj.202401604RRR","DOIUrl":"https://doi.org/10.1096/fj.202401604RRR","url":null,"abstract":"<p>COVID-19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting a detrimental impact of SARS-CoV-2 or the viral Spike protein on the central nervous system. Nonetheless, the molecular pathway behind neurological pathology and the presumed neurotropism of SARS-CoV-2 remains largely unexplored. We generated human cortical organoids (HCOs) derived from human induced pluripotent stem cells (hiPSC) to assess: (1) the expression of SARS-CoV-2 main entry factors; (2) their vulnerability to SARS-CoV-2 infection; and (3) the impact of SARS-CoV-2 infection and exposure to the Spike protein on their transcriptome. Results proved that (1) HCOs express the main SARS-CoV-2 receptors and co-receptors; (2) HCOs may be productively infected by SARS-CoV-2; (3) the viral particles released by SARS-CoV-2-infected HCOs are able to re-infect another cellular line; and (4) the infection resulted in the activation of apoptotic and stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when HCOs were exposed to the Spike protein alone. The data obtained demonstrate that SARS-CoV-2 likely infects HCOs probably through the binding of ACE2, CD147, and NRP1 entry factors. Furthermore, exposure to the Spike protein alone proved sufficient to disrupt their homeostasis and induce neurotoxic effects, potentially contributing to the onset of long-COVID symptoms.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401604RRR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of O-GlcNAcylation regulating liver lipid synthesis in mice through FASN","authors":"Xiaoshuang Li,&nbsp;Ziyang Zhang,&nbsp;Meng Zhang,&nbsp;Yu Cao,&nbsp;Wanhui Zhou,&nbsp;Lele Kou,&nbsp;Wenjin Guo,&nbsp;Boxi Zhang,&nbsp;Shize Li,&nbsp;Bin Xu","doi":"10.1096/fj.202402451RR","DOIUrl":"https://doi.org/10.1096/fj.202402451RR","url":null,"abstract":"<p>Nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases. O-Linked attachment of beta-N-acetylglucosamine (<i>O</i>-GlcNAc) are ubiquitous post-translational modifications of proteins as “nutrient sensors” and “stress receptors” in the body that are involved in maintaining normal cellular physiological functions. Increased levels of <i>O</i>-GlcNAcylation have been found in the liver samples of patients with NAFLD and nonalcoholic steatohepatitis. However, the role of <i>O</i>-GlcNAcylation in the development and pathogenesis of NAFLD remains unclear. Here, we sought to determine the specific role of <i>O</i>-GlcNAcylation in NAFLD. In this study, the results demonstrated that inhibition of <i>O</i>-GlcNAc transferase (OGT) led to decreased expression of liver lipid synthesis genes and proteins in vitro. In addition, we showed that fatty acid synthase (FASN) expression was positively correlated with <i>O</i>-GlcNAcylation levels. Immunoprecipitation and pulldown assays confirmed the interaction between FASN and OGT at the serine 1483 of FASN, to inhibit K48-linked ubiquitination and degradation of FASN, thereby promoting hepatic lipid accumulation and the development of NAFLD. Administration of the OGT inhibitor OSMI-1 to ob/ob mice led to decreased liver lipid accumulation, further confirming our in vitro experimental results. Finally, we used liver-specific <i>Ogt</i> gene knockout mice fed a high-fat diet to elucidate the specific mechanism of <i>O</i>-GlcNAcylation on NAFLD and found that knockdown of the <i>Ogt</i> gene led to decreased liver lipid accumulation. In conclusion, our findings show that inhibiting the <i>O</i>-GlcNAcylation of FASN at the S1483 site promotes the K48-linked ubiquitination and degradation of FASN and leads to inhibition of lipid accumulation in the liver. Treatment with the OGT inhibitor OSMI-1 leads to decreased lipid accumulation in the liver, suggesting that targeting <i>O</i>-GlcNAcylation sites could be a potential therapeutic strategy for alleviating NAFLD.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An immunoregulatory amphipathic peptide derived from Fasciola hepatica helminth defense molecule (FhHDM-1.C2) exhibits potent biotherapeutic activity in a murine model of multiple sclerosis","authors":"Richard Lalor,&nbsp;Akane Tanaka,&nbsp;Jenna Shiels,&nbsp;Aakanksha Dixit,&nbsp;Sabine Hoadley,&nbsp;Eloïse Dufourd,&nbsp;Siobhan Hamon,&nbsp;Joyce To,&nbsp;Clifford C. Taggart,&nbsp;Sinead Weldon,&nbsp;Bronwyn O'Brien,&nbsp;Judith Greer,&nbsp;John P. Dalton,&nbsp;Sheila Donnelly","doi":"10.1096/fj.202400793RR","DOIUrl":"https://doi.org/10.1096/fj.202400793RR","url":null,"abstract":"<p>The helminth defense molecules (HDM) are a family of immune regulatory peptides exclusively expressed by trematode worms. We have previously demonstrated that in vivo FhHDM-1, the archetypal member of the HDMs, regulated macrophage responses to inflammatory ligands, thereby ameliorating the progression of immune-mediated tissue damage in several murine models of inflammatory disease. Accordingly, we postulated that an understanding of the structure–function relationship of the HDMs would facilitate the identification of the minimal bioactive peptide, which would represent a more synthesizable, cost-effective, potent biotherapeutic. Thus, using a combination of bioinformatics, structural analyses, and cellular assays we discovered a 40 amino acid peptide derivative termed FhHDM-1.C2. This peptide contains a 12 amino acid motif at its N-terminus, which facilitates cellular interaction and uptake, and an amphipathic α-helix within the C-terminus, which is necessary for lysosomal vATPase inhibitory activity, with both regions linked by a short unstructured segment. The FhHDM-1.C2 peptide exhibits enhanced regulation of macrophage function, compared with the full-length FhHDM-1, and potent prevention of the progression of relapsing–remitting-experimental autoimmune encephalomyelitis (EAE) when administered prophylactically or therapeutically. The protective effect of FhHDM-1.C2 is not associated with global immune suppression, which places the HDMs peptides as an improved class of biotherapeutics for the treatment of inflammatory diseases. Comparing the HDMs from several zoonotic trematodes revealed a similar capacity for immune regulation. These important new advances into the structure–function relationship of the lead HDM peptide, FhHDM-1, encourage further prospecting and screening of the broader trematode family of peptides for the discovery of novel and potent immune-biotherapeutics.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202400793RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoantibodies targeting angiotensin-converting enzyme 2 are prevalent and not induced by SARS-CoV-2 infection","authors":"Yannick Galipeau,&nbsp;Nicolas Castonguay,&nbsp;Pauline S. McCluskie,&nbsp;Mayra Trentin Sonoda,&nbsp;Alexa Keeshan,&nbsp;Erin Collins,&nbsp;Corey Arnold,&nbsp;Martin Pelchat,&nbsp;Kevin Burns,&nbsp;Curtis Cooper,&nbsp;Marc-André Langlois","doi":"10.1096/fj.202402694R","DOIUrl":"https://doi.org/10.1096/fj.202402694R","url":null,"abstract":"<p>Clinical outcomes resulting from SARS-CoV-2 infection vary widely, ranging from asymptomatic cases to the development of mild to severe respiratory illness, and in some instances, chronic lingering disease and mortality. The underlying biological mechanisms driving this wide spectrum of pathogenicity among certain individuals and demographics remain elusive. Autoantibodies have emerged as potential contributors to the severity of COVID-19. Although preliminary reports have suggested the induction of antibodies targeting Angiotensin-Converting Enzyme II (ACE2) post-infection, this assertion lacks confirmation in large-scale studies. In this study, our objective is to comprehensively characterize and quantify the prevalence and expression levels of autoantibodies directed against ACE2 in a sizable cohort (<i>n</i> = 464). Our findings reveal that ACE2-reactive IgM antibodies are the most prevalent, with an overall seroprevalence of 18.8%, followed by IgG at 10.3% and IgA at 6.3%. Longitudinal analysis of individuals with multiple blood draws showed stable ACE2 IgG and IgA levels over time. Upon stratifying individuals based on molecular testing for SARS-CoV-2 or serological evidence of past infection, no significant differences were observed between groups. Functional assessment of ACE2 autoantibodies demonstrated that they are non-neutralizing and failed to inhibit spike-ACE2 interaction or affect the enzymatic activity of ACE2. Our results highlight that ACE2 autoantibodies are prevalent in the general population and were not induced by SARS-CoV-2 infection in our cohort. Notably, we found no substantiated evidence supporting a direct role for ACE2 autoantibodies in SARS-CoV-2 pathogenesis.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402694R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell cycle-based antibody selection for suppressing cancer cell growth","authors":"Chi Hun Song,&nbsp;Chih-Wei Lin,&nbsp;Kyung Ho Han","doi":"10.1096/fj.202401586RRR","DOIUrl":"https://doi.org/10.1096/fj.202401586RRR","url":null,"abstract":"<p>Cell cycle arrest and programmed cell death are crucial biological processes in cancer development. Regulating cell fate decisions is essential due to their potential to induce cell cycle arrest and cell death. Inducing cell cycle regulatory proteins in tumor cells is considered a key objective in cancer therapy. Here, we present a novel method that selects antibodies from an antibody library to inhibit cancer growth using fluorescence-activated cell sorting (FACS) assays and cell cycle analysis. This approach seeks antibodies that induce cancer cells to enter the G0 or G1 phase, a quiescent state where cells cease to proliferate and trigger programmed cell death. We found that the T1 antibody effectively suppresses the proliferation of cancer cells. Mechanistically, serine protease 3 (PRSS3) is a target antigen of the T1 antibody. We demonstrated that PRSS3 controls tumor cell proliferation and apoptosis through interaction with the T1 antibody. This research suggests that PRSS3 holds great potential as a target for solid cancer treatment. This cycle-based approach to antibody screening shows potential because it can be broadly applied to cancer and other challenging diseases.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the role of KLF9-mediated IFITM3 regulation in amyloidogenesis","authors":"Yijia Feng,&nbsp;Qian Zhou,&nbsp;Bolang Hu,&nbsp;Shengya Wang,&nbsp;Lifen Chen,&nbsp;Wantong Cai,&nbsp;Qinxin Zhu,&nbsp;Xuemei Qin,&nbsp;Weihui Zhou,&nbsp;Yili Wu,&nbsp;Weihong Song","doi":"10.1096/fj.202401584RR","DOIUrl":"https://doi.org/10.1096/fj.202401584RR","url":null,"abstract":"<p>Interferon-induced transmembrane protein 3 (IFITM3) is implicated in the pathogenesis of Alzheimer's Disease (AD) by regulating γ-secretase activity and subsequent amyloid β (Aβ) generation. However, the regulation of <i>IFITM3</i> gene expression and the underlying mechanisms remain exclusive. In this study, we aimed to investigate the regulation of the IFITM3 and its role in amyloidogenesis. The functional active promoter of the <i>IFITM3</i> gene was identified within the 1047 bp of 5′-flanking regions by luciferase assays. Through chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA), we successfully identified a specific Krüppel-like factor 9 (KLF9) binding site within the promoter region. Moreover, KLF9 overexpression significantly upregulates IFITM3 expression in vitro and in vivo, which promotes Aβ generation in the hippocampus of mice. Consistently, reduced IFITM3 expression results in a notable decrease of Aβ production. Together, we demonstrate that KLF9 plays a critical role in regulating IFITM3 expression and subsequent Aβ production. It highly suggests that inhibiting KLF9-mediated IFITM3 expression may have therapeutic potential for AD by reducing Aβ production.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Swi6/HP1 binding motif in its partner protein reveals the basis for the functional divergence of the HP1 family proteins in fission yeast","authors":"Tomoyuki Oya,&nbsp;Mayo Tanaka,&nbsp;Aki Hayashi,&nbsp;Yuriko Yoshimura,&nbsp;Rinko Nakamura,&nbsp;Kyohei Arita,&nbsp;Yota Murakami,&nbsp;Jun-ichi Nakayama","doi":"10.1096/fj.202402264RR","DOIUrl":"https://doi.org/10.1096/fj.202402264RR","url":null,"abstract":"<p>The heterochromatin protein 1 (HP1) family recognizes lysine 9-methylated histone H3 (H3K9me) and recruits other transacting factors to establish higher order chromatin structures. In the fission yeast <i>Schizosaccharomyces pombe</i> (<i>S. pombe</i>), two HP1 family proteins, Swi6 and Chp2, play distinct roles in recruiting transacting factors: Swi6 primarily recruits Epe1, a Jumonji C domain-containing protein involved in histone H3K9 demethylation, whereas Chp2 recruits Mit1, a component of the Snf2/Hdac Repressive Complex. However, detailed mechanisms of how multiple HP1 family proteins and their respective interactors work cooperatively or exclusively to form higher order chromatin structures remain elusive. In this study, we investigated the interactions between Swi6 and Epe1. We found that Swi6 interacts with Epe1 through its chromoshadow domain, and identified a unique motif, named the FVI motif, in Epe1 involved in this interaction through detailed mapping of the region. Enhanced green fluorescent protein (EGFP) tethering assays showed that the FVI motif is sufficient to recruit ectopically expressed EGFP to heterochromatic regions, and mutational analyses revealed that conserved hydrophobic residues in this motif are essential for proper targeting. Structural simulations further supported the importance of these residues in Swi6 binding. Interestingly, Mit1 containing the Epe1 FVI motif was recruited to the heterochromatic regions by Swi6 but not by Chp2. Cells expressing mutant Mit1 maintained heterochromatic silencing even in <i>chp2</i>∆ cells, suggesting that Chp2 is not required for heterochromatin formation when Mit1 is recruited by Swi6. These findings highlight distinct HP1-binding motifs in interactors, contributing to functional divergence among HP1 family proteins.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402264RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Granulosa cell expression of Fos is critical for regulating ovulatory gene expressions in the mouse ovary","authors":"Jacqueline Southall,&nbsp;Shawn Park,&nbsp;Yohan Choi,&nbsp;Hayce Jeon,&nbsp;Chemyong Ko,&nbsp;Misung Jo","doi":"10.1096/fj.202402867R","DOIUrl":"https://doi.org/10.1096/fj.202402867R","url":null,"abstract":"<p>A previous study showed that female <i>Fos</i> null mice fail to ovulate even when given gonadotropins, suggesting that ovarian expression of <i>Fos</i> is critical for successful ovulation. However, the expression of FOS and function of FOS have not been determined in the mouse ovary. FOS, a member of the Fos family (<i>Fos, Fosb, Fosl1</i>, and <i>Fosl2</i>), functions as a transcription factor by forming a heterodimer complex with a member of Jun family (<i>Jun, Junb</i>, and <i>Jund</i>). This study demonstrated rapid increases in <i>Fos</i>, along with other Fos and Jun family members, after hCG administration in the ovary of immature PMSG-primed mice and after the LH surge in naturally cycling animals. ChIP-seq analysis identified 1965 FOS-binding genes in granulosa cells collected at 3 h post-hCG, including <i>Pgr</i>, <i>Ptgs2, Tnfiap6</i>, and <i>Edn2</i>, genes known to be involved in the ovulatory process. When super-ovulation was induced, the number of oocytes released was significantly reduced in <i>Esr2</i>^<i>cre/+</i>-driven granulosa cell-specific <i>Fos</i> knockout (<i>gcFos</i>KO) mice. This reduction was accompanied by lower expressions of <i>Pgr, Ptgs2, Ptgs1,</i> and <i>Edn2</i> in preovulatory follicles of <i>gcFosKO</i> mice compared to those in control littermates. In addition, <i>gcFos</i>KO mice showed a trend toward a decreased average litter size. Together, the present study indicates that the preovulatory induction of <i>Fos</i> expression is crucial for increasing the expression of key ovulatory genes, yet the role of FOS may be partially substituted by other <i>Fos</i> and <i>Jun</i> family members induced in the preovulatory follicle in the <i>gcFos</i>KO mouse ovary.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}