Journal of Molecular Medicine-Jmm最新文献

{"title":"Drosophila modeling to identify causative genes and reveal the underlying molecular mechanisms for primary ovarian insufficiency.","authors":"Yanbin Ma, Yuxin Liu, Man Xu, Xinhuan Yin, Chenyu Hu, Xiaohang Yang, Wanzhong Ge","doi":"10.1007/s00109-025-02516-1","DOIUrl":"10.1007/s00109-025-02516-1","url":null,"abstract":"<p><p>Primary ovarian insufficiency (POI) is a disease defined as a reduction in ovarian function under the age of 40 and represents the main cause of female infertility. In recent years, many genetic mutations associated with POI have been identified using high-throughput sequencing technology. However, one big challenge today is to determine the disease-causing gene associations through functional assessment. Here, we develop a Drosophila model to study the POI-associated genes and provide in vivo functional evidence to validate the POI-causing genes. We use two different Gal4 drivers, in combination with RNAi transgene, and systematically knockdown 51 genes associated with POI. We show that 22 and 17 genes are required for female fertility and ovarian development in somatic and germline cells, respectively. Moreover, we also focus on AlaRS-m, the Drosophila ortholog of the human AARS2 gene, for further functional characterization. Depletion of AlaRS-m in ovarian somatic cells leads to decreased female fertility and a reduction in ovary size, as well as egg chamber degeneration. We also provide evidence that AlaRS-m deficiency causes mitochondrial dysfunction, overproduction of ROS, and apoptotic cell death. Our findings demonstrate that Drosophila can be used as a platform to assess the functional significance of POI-associated genes identified in genomic studies and illustrate the molecular mechanism underlying the pathogenesis of POI. KEY MESSAGES: • One hundred fourteen genes associated with POI are identified, and 76 of them have Drosophila orthologs. • Twenty-two genes and 17 genes are required for female fertility when knocked down in the Drosophila ovarian somatic cells and germline cells, respectively. • AlaRS-m/AARS2 deficiency causes female fertility defects with egg chamber degeneration.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"239-253"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indole-3-Aldehyde alleviates lung inflammation in COPD through activating Aryl Hydrocarbon Receptor to inhibit HDACs/NF-κB/NLRP3 signaling pathways.","authors":"Pengtao Wang, Wei Tao, Qiujie Li, Wanting Ma, Wei Jia, Yuting Kang","doi":"10.1007/s00109-024-02506-9","DOIUrl":"10.1007/s00109-024-02506-9","url":null,"abstract":"<p><p>Indole-3-aldehyde (I3A) is an intestinal microbial metabolite that regulates inflammation in various inflammatory diseases; however, its role in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the anti-inflammatory effects and molecular mechanisms of I3A in COPD. We constructed in vivo models using cigarette smoke (CS)-stimulated mice and in vitro models using cigarette smoke extract (CSE)-stimulated MH-S cells. The results demonstrated that I3A significantly alleviated bronchial obstruction in mice with COPD and reduced the expression of inflammatory factors such as TNF-α, IL-1β, and IL-6. Additionally, I3A decreased the levels of matrix metalloproteinases MMP2, MMP12, and inhibited the NF-κB p65/NLRP3 pathways. Further investigation revealed that I3A inhibited NF-κB activity by suppressing p65 phosphorylation and nuclear translocation in CSE-stimulated MH-S cells. The activation of the NF-κB and NLRP3 signaling pathways is mediated by histone deacetylase 5 (HDAC5) and HDAC6, both of which are inhibited by I3A. Subsequent experiments indicated that aryl hydrocarbon receptor (AHR) knockdown attenuated the inhibitory effect of I3A on pro-inflammatory cytokines and the HDACs/NF-κB/NLRP3 signaling pathways, highlighting the dependence of I3A's anti-inflammatory effects on the AHR receptor. KEY MESSAGES: I3A effectively reduced lung inflammation in COPD mice by inhibiting the NF-κB pathway. In CSE-stimulated MH-S cells, I3A suppressed p65 phosphorylation and nuclear translocation, thereby inhibiting NF-κB activity. The activation of the NF-κB/NLRP3 pathways by HDAC5 and HDAC6 was diminished by I3A. Through the activation of the AHR receptor, I3A suppressed the activities of HDAC5/6, leading to a decrease in inflammatory factor levels.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"157-174"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular characterization of ovarian squamous cell carcinoma originating from mature teratoma.","authors":"Angel Chao, Chyong-Huey Lai, An-Shine Chao, Chiao-Yun Lin, You-Chen Wang, Huei-Jean Huang, Ren-Chin Wu","doi":"10.1007/s00109-024-02505-w","DOIUrl":"10.1007/s00109-024-02505-w","url":null,"abstract":"<p><p>Squamous cell carcinoma (SCC) of the ovary, an uncommon form of gynecologic cancer, typically originates from the malignant transformation of a pre-existing mature ovarian teratoma (MOT). However, due to its rarity, the molecular pathways driving its development are not well understood. To address this knowledge gap, we performed molecular inversion probe (MIP) array analysis and targeted sequencing of 275 cancer susceptibility genes on 11 ovarian SCC samples derived from MOTs. Additionally, we conducted the same molecular tests on two samples of ovarian metastases of SCCs that originated from primary sites outside the ovary, specifically, one from endometrial cancer and one from cervical SCC. Utilizing MIP arrays, we identified failures in meiosis I and II, as well as instances of endoreduplication within haploid ova, in five, two, and four samples of ovarian SCCs arising from MOTs, respectively. Notably, such alterations were absent in samples of ovarian metastases, implying that primary ovarian SCCs may derive from teratoma cells. Targeted sequencing identified TP53 as the most frequently mutated gene in ovarian SCCs, occurring in 82% of cases. This was followed by mutations in PIK3CA (36%), PTEN (27%), and KMT2D (27%). Furthermore, mutations in CDKN2A and copy number loss of 9p21.3 were observed in 54.5% of the cohort. In summary, our study elucidates the germ cell origin of ovarian SCC and provides a comprehensive analysis of its genomic landscape, which may assist in differential diagnosis and inform the development of targeted therapies with potential clinical benefits. KEY MESSAGES: Failures in meiosis I/II and endoreduplication found in primary ovarian SCCs.  Ovarian SCCs may derive from germ cells in mature teratomas.  Alterations absent in ovarian metastases from SCC aid differential diagnosis. TP53 mutations found in 82% of ovarian SCC cases. CDKN2A mutations and 9p21.3 loss observed in 54.5% of ovarian SCC cohort.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"101-111"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central dopamine receptors: Radiotracers unveiling the Role of dopaminergic tone in obesity.","authors":"Marta Lapo Pais, Joana Crisóstomo, Antero Abrunhosa, Miguel Castelo-Branco","doi":"10.1007/s00109-024-02501-0","DOIUrl":"10.1007/s00109-024-02501-0","url":null,"abstract":"<p><p>Brain dopamine type 2 and 3 receptors (D2/3R) have been postulated to play a role in obesity. However, results from molecular neuroimaging studies exploring these receptors in obesity are not consensual. These inconsistencies may be due to the distinct characteristics of radiotracers that confound the interpretation of D2/3R assessment. Only three meta-analyses reported their results across radiotracers. Although all agree that obesity severity influences D2/3R availability, results vary for [¹¹C]raclopride. Further, D2/3R assessment has been commonly interpreted as reflecting receptor density or availability. An alternative interpretation could be related to changes in endogenous central dopaminergic tone. The main question is whether the hypothesis of a quadratic relationship between dopaminergic tone and degree of obesity is suitable for the distinct characteristics of radiotracers. To answer this question and clarify the role of dopaminergic tone in obesity, we systematically reviewed this issue across radiotracers. Out of 514 articles, 15 articles were selected for review. Besides obesity severity, this study highlights the influence of radiotracer characteristics when assessing D2/3R. The tested hypothesis proved to be more suitable for radiotracers more susceptible to endogenous dopamine or with a lower affinity to D2/3R, supporting the quadratic relationship between dopaminergic tone and degree of obesity. While the role of D2/3R density in obesity may be relevant, dopaminergic tone seems to have a greater impact on the obesity-related differences found in these receptors. Finally, neuropsychological factors should be tested in addition to body mass index, as they may better reflect altered brain dopaminergic function.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"21-32"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of iron overload in human joint tissue explant cultures and animal models.","authors":"Indira Prasadam, Karsten Schrobback, Bastian Kranz-Rudolph, Nadine Fischer, Yogita Sonar, Antonia RuJia Sun, Eriza Secondes, Travis Klein, Ross Crawford, V Nathan Subramaniam, Gautam Rishi","doi":"10.1007/s00109-024-02495-9","DOIUrl":"10.1007/s00109-024-02495-9","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a prevalent degenerative joint disease affecting over 530 million individuals worldwide. Recent studies suggest a potential link between iron overload, a condition characterised by the excessive accumulation of iron in the body, and the onset of OA. Iron is essential for various biological processes, and any disruption in its homeostasis can trigger significant health effects, including OA. This study aimed to elucidate the effects of excess iron on joint tissue and the underlying mechanisms associated with excess iron and OA development. Human articular cartilage (n = 6) and synovium (n = 4) were collected from patients who underwent total knee arthroplasty. Cartilage and synovium explants were incubated with a gradually increasing concentration of ferric ammonium citrate for 3 days respectively. The effects of iron homeostasis in tissue explants were analysed using a Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS). To further study the effects of iron excess on OA initiation and development, male 3-week-old Hfe^-/- and 5-week-old Tfr2^-/- mice, animal models of hereditary haemochromatosis were established. Littermate wild-type mice were fed a high-iron diet to induce dietary overload. All animals were sacrificed at 8 weeks of age, and knee joints were harvested for histological analysis. The LA-ICP-MS analysis unveiled changes in the elemental composition related to iron metabolism, which included alterations in FTH1, FPN1, and HAMP within iron(III)-treated cartilage explants. While chondrocyte viability remained stable under different iron concentrations, ex vivo treatment with a high concentration of Fe³⁺ increased the catabolic gene expression of MMP13. Similar alterations were observed in the synovium, with added increases in GAG content and inflammation markers. In vivo studies further supported the role of iron overload in OA development as evidenced by spontaneous OA symptoms, proteoglycan loss, increased Mankin scores, synovial thickening, and enhanced immunohistochemical expression of MMP13, ADAMTS5, and P21 in Hfe^-/-, Tfr2^-/-, and diet-induced iron overload mouse models. Our findings elucidate the specific pathways through which excess iron accelerates OA progression and highlights potential targets for therapeutic intervention aimed at modulating iron levels to mitigate OA symptoms. KEY MESSAGES: Iron overload alters joint iron metabolism, increasing OA markers in cartilage and synovium. High iron levels in mice accelerate OA, highlighting genetic and dietary impacts. Excess iron prompts chondrocyte iron storage response, signalling potential OA pathways. Iron dysregulation linked to increased cartilage degradation and synovial inflammation. Our findings support targeted therapies for OA based on iron modulation strategies.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"73-86"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of ceRNAs in breast cancer microenvironmental regulation and therapeutic implications.","authors":"Alper Yilmaz, Selcen Ari Yuka","doi":"10.1007/s00109-024-02503-y","DOIUrl":"10.1007/s00109-024-02503-y","url":null,"abstract":"<p><p>The tumor microenvironment, which is the tailored physiological milieu of heterogeneous cancer cell populations surrounded by stromal and immune cells as well as extracellular matrix components, is a leading modulator of critical cancer hallmarks and one of the most significant prognostic indicators in breast cancer. In the last few decades, with the discovery of the interactions of ncRNAs with diverse cellular molecules, considerable emphasis has been devoted to understanding their direct and indirect roles in specific functions in breast cancer. Collectively, all of these have revealed that the competitive action of protein-coding RNAs and ncRNAs such as circRNAs and lncRNAs, which have a shared affinity for miRNAs, play a vital role in the molecular regulation of breast cancer. This phenomenon, termed as competing endogenous RNAs (ceRNAs), facilitates modeling the microenvironment through intercellular shuttles. Microenvironment ceRNA interactions have emerged as a frontier in the deep understanding of the complex mechanisms of breast cancer. In this review, we first discuss cellular ceRNAs in four key biological processes critical for microenvironmental regulation in breast cancer tissues: hypoxia, angiogenesis, immune regulations, and ECM remodeling. Further, we draw a complete portrait of microenvironment regulation by cell-to-cell cross-talk of shuttled ceRNAs and offer a framework of potential applications and challenges in overcoming the aggressive phenotype of the breast cancer microenvironment.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"33-49"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of inhibitory immune checkpoint receptors in the pathogenesis of Alzheimer's disease.","authors":"Antero Salminen","doi":"10.1007/s00109-024-02504-x","DOIUrl":"10.1007/s00109-024-02504-x","url":null,"abstract":"<p><p>There is mounting evidence that microglial cells have a key role in the pathogenesis of Alzheimer's disease (AD). In AD pathology, microglial cells not only are unable to remove β-amyloid (Aβ) plaques and invading pathogens but also are involved in synaptic pruning, chronic neuroinflammation, and neuronal degeneration. Microglial cells possess many different inhibitory immune checkpoint receptors, such as PD-1, LILRB2-4, Siglecs, and SIRPα receptors, which can be targeted by diverse cell membrane-bound and soluble ligand proteins to suppress the functions of microglia. Interestingly, in the brains of AD patients there are elevated levels of many of the inhibitory ligands acting via these inhibitory checkpoint receptors. For instance, Aβ oligomers, ApoE4, and fibronectin are able to stimulate the LILRB2-4 receptors. Increased deposition of sialoglycans, e.g., gangliosides, inhibits microglial function via Siglec receptors. AD pathology augments the accumulation of senescent cells, which are known to possess a high level of PD-L1 proteins, and thus, they can evade immune surveillance. A decrease in the expression of SIRPα receptor in microglia and its ligand CD47 in neurons enhances the phagocytic pruning of synapses in AD brains. Moreover, cerebral neurons contain inhibitory checkpoint receptors which can inhibit axonal growth, reduce synaptic plasticity, and impair learning and memory. It seems that inappropriate inhibitory immune checkpoint signaling impairs the functions of microglia and neurons thus promoting AD pathogenesis. KEY MESSAGES: Microglial cells have a major role in the pathogenesis of AD. A decline in immune activity of microglia promotes AD pathology. Microglial cells and neurons contain diverse inhibitory immune checkpoint receptors. The level of ligands for inhibitory checkpoint receptors is increased in AD pathology. Impaired signaling of inhibitory immune checkpoint receptors promotes AD pathology.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1-19"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142734354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular and cellular landscape of hypertrophic cardiomyopathy phenotypes: transition from obstructive to end-stage heart failure.","authors":"Jude Taylor, Sean Lal, Filip Braet, Craig S McLachlan, Amy Li","doi":"10.1007/s00109-024-02508-7","DOIUrl":"10.1007/s00109-024-02508-7","url":null,"abstract":"<p><p>Hypertrophic cardiomyopathy (HCM) is a myocardial disorder which commonly presents as an obstructive or end-stage disease. This study aims to investigate the transcriptomic changes related to cardiac cell-specific expression profiles that underpin the molecular transition between the HCM phenotypes. This study utilizes bioinformatics meta-analysis to integrate independent datasets to generate a comprehensive gene expression profile of obstructive HCM and end-stage HCM phenotypes compared to donor hearts. Gene set enrichment and cellular deconvolution were applied to identify ontologies and pathways related to each phenotype and to enumerate cell abundances. The intersection between cell lineage genes and meta-genes was identified to explore the cellular contribution to the phenotypic molecular signatures. Meta-analysis revealed, enhanced muscle function and myocardial remodeling, alongside impaired immune and inflammatory processes in obstructive HCM. In contrast, enriched tissue matrix remodeling pathways and altered metabolic and signaling cascades were identified in end-stage HCM, indicating a shift towards cellular dysfunction and loss of homeostasis. These molecular profiles were associated with an altered cellular landscape, with increased cardiomyocytes and lower immune cell populations in obstructive samples but increased fibroblasts and smooth muscle cells in end-stage HCM, implicating extensive tissue remodeling. This study provides novel insights into the cellular contributions of contractile, immune, homeostatic, and vascular alterations underpinning each of the HCM phenotypes. KEY MESSAGES: HCM phenotypes are characterized by distinct molecular and cellular profiles. Obstructive HCM has an enriched contractile profile underpinned by an expanded cardiomyocyte population. End-stage HCM shifts the cellular profile towards extracellular and vascular remodeling.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"113-123"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of STAT3 and MYC as critical ferroptosis-related biomarkers in septic cardiomyopathy: a bioinformatics and experimental study.","authors":"Fangyu Liu, Qian Wang, Haoran Ye, Yuan Du, Mingjiao Wang, Yuhong Guo, Shasha He","doi":"10.1007/s00109-024-02502-z","DOIUrl":"10.1007/s00109-024-02502-z","url":null,"abstract":"<p><p>Ferroptosis is the well-known mechanism of septic cardiomyopathy (SCM). Bioinformatics analysis was employed to identify ferroptosis-related SCM differentially expressed genes (DEG). DEGs' functional enrichment was explored. Weighted gene co-expression network analysis (WGCNA) was employed to form gene clusters. The identified hub genes, signal transducer and activator of transcription 3 (STAT3) and myelocytomatosis (MYC) were further evaluated by generating receiver operator characteristic (ROC) curves and a nomogram prediction model. Additionally, survival rate, cardiac damage markers, and cardiac function and ferroptosis markers were evaluated in septic mouse model. STAT3 and MYC levels were measured in SCM heart tissue via immunohistochemical (IHC) staining, real-time polymerase chain reaction (qPCR) and western blot analysis. Analysis identified 225 DEGs and revealed 22 intersected genes. Of the 7 hub genes, STAT3 and MYC showed enrichment in septic heart tissue and a strong predicative ability based on AUC values. Cardiac damage, iron metabolism, and lipid peroxidation occurred in the SCM model. By experiments, STAT3 and MYC expression was increased in the SCM model. Impairment was reversed with a ferroptosis inhibitor, Fer-1. As conclusion, STAT3 and MYC are related with ferroptosis and may serve as potential SCM predictor indicators. KEY MESSAGES: Septic cardiomyopathy (SCM) often leads to high mortality in septic patients, and the diagnostic criteria still remains unclear. Ferroptosis as the pathogenic mechanism of SCM could help predict its progression and clinical outcomes. STAT3 and MYC are related with ferroptosis and may serve as potential SCM predictor biomarkers.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"87-100"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Manic Fringe promotes endothelial-to-mesenchymal transition mediated by the Notch signalling pathway during heart valve development.","authors":"Junjie Yang, Zhi Wang, Yue Zhou, Shiwei Jiang, Xiji Qin, Zhikang Xu, Yu Wang, Mengying Zuo, Zhuo Meng, Sun Chen, Qingjie Wang, Jian Wang, Kun Sun","doi":"10.1007/s00109-024-02492-y","DOIUrl":"10.1007/s00109-024-02492-y","url":null,"abstract":"<p><p>A fundamental event in the formation of heart valves involves the transformation of endocardial cells within the outflow tract (OFT) and atrioventricular canal (AVC) cushions through a process known as endothelial-to-mesenchymal transition (EndMT). Aberrant EndMT is a primary cause of congenital valvular malformations. Manic Fringe (MFNG) has been previously associated with cardiovascular development, although its role in heart valve development remains underexplored. In this study, we seek to enhance our understanding of MFNG's involvement in valve formation and its association with EndMT. Staining results of histological section revealed the expression of MFNG in the AVC and OFT from embryonic day 9.5 to 10.5 (E9.5-E10.5), when EndMT takes place. Cellular data demonstrated that MFNG exerts a positive regulatory influence on the EndMT process, promoting endothelial cell (EC) migration by enhancing the activity of the Notch signalling pathway. MFNG knockdown mediated by antisense morpholino oligonucleotides (MO) injection caused abnormal development of the heart and valves in zebrafish. Furthermore, through whole-exome sequencing (WES), we identified a heterozygous MFNG mutation in patients diagnosed with tetralogy of Fallot-pulmonary valve stenosis (TOF-PS). Cellular and molecular assays confirmed that this deleterious mutation reduced MFNG expression and hindered the EndMT process. In summary, our study verifies that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway during the heart and valve development. The MFNG deleterious variant induces MFNG loss of function, potentially elucidating the underlying molecular mechanisms of MFNG's involvement in the pathogenesis of congenital heart valve defects. These observations contribute to our current genetic understanding of congenital heart valve disease and may provide a potential target for prenatal diagnosis and treatment. KEY MESSAGES: Our examination revealed, for the first time, that MFNG exhibited high expression levels during EndMT of heart valve development in mice. Our findings provide compelling evidence that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway. Our results identified, for the first time, a deleterious MFNG p. T77M variant that inhibited the EndMT process by downregulating the activity of the Notch signalling pathway, thereby preventing the normal valve formation. MFNG may serve as an early diagnostic marker and an effective therapeutic target for the clinical treatment of congenital heart valve defects.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"51-71"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}