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Deleterious variants in RNF111 impair female fertility and induce premature ovarian insufficiency in humans and mice

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Science China(Life Sciences) 2024年第7期67卷 1325-1337页

作者： Chengcheng Song Yingying Qin Yan Li Bingyi Yang Ting Guo Wenqing Ma Dian Xu Keyan Xu Fangfang Fu Li Jin Yanhua Wu Shuyan Tang Xiaojun Chen Feng Zhang Obstetrics and Gynecology Hospital State Key Laboratory of Genetic EngineeringInstitute of Medical Genetics and GenomicsFudan UniversityShanghai 200011China Human Phenome Institute Zhangjiang Fudan International Innovation CenterFudan UniversityShanghai 201203China center for reproductive medicine Cheeloo College of MedicineShandong UniversityJinan 250021China State Key Laboratory of reproductive medicine and Offspring Health Key Laboratory of Reproductive Endocrinology of Ministry of EducationNational Research Center for Assisted Reproductive Technology and Reproductive GeneticsShandong Key Laboratory of Reproductive MedicineShandong Provincial Clinical Research Center for Reproductive HealthShandong UniversityJinan 250021China Department of Obstetrics and Gynecology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China National Demonstration center for Experimental Biology Education School of Life SciencesFudan UniversityShanghai 200433China Department of Gynecology the Tenth People’s Hospital of Tongji UniversityShanghai 200072China Soong Ching Ling Institute of Maternity and Child Health International Peace Maternity and Child Health Hospital of China Welfare InstituteShanghai 200030China

Premature ovarian insufficiency(POI)is a heterogeneous female disorder characterized by the loss of ovarian function before the age of *** represents a significant detriment to female ***,the known POI-causative genes currently account for only a fraction of *** elucidate the genetic factors underlying POI,we conducted whole-exome sequencing on a family with three fertile POI patients and identified a deleterious missense variant in *** a subsequent replication study involving 1,030 POI patients,this variant was not only confirmed but also accompanied by the discovery of three additional predicted deleterious RNF111 *** variants collectively account for eight cases,representing 0.78%of the study cohort.A further study involving 500 patients with diminished ovarian reserve also identified two additional RNF111 ***,RNF111 encodes an E3 ubiquitin ligase with a regulatory role in the TGF-β/BMP signaling *** analysis revealed that RNF111/RNF111 is predominantly expressed in the oocytes of mice,monkeys,and *** further investigate the functional implications of RNF111 variants,we generated two mouse models:one with a heterozygous missense mutation(Rnf111+/M)and another with a heterozygous null mutation(Rnf111^(+/-)).Both mouse models exhibited impaired female fertility,characterized by reduced litter sizes and small ovarian ***,RNA-seq and quantitative proteomics analysis unveiled that Rnf111 haploinsufficiency led to dysregulation in female gonad development and negative regulation of the BMP signaling pathway within mouse *** conclusion,our findings strongly suggest that monoallelic deleterious variants in RNF111 can impair female fertility and induce POI in both humans and mice.

关键词： POI RNF111 female fertility ovarian reserve

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Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

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Protein & Cell 2024年第5期15卷 364-384页

作者： Huifen Lu Ying Jing Chen Zhang Shuai Ma Weiqi Zhang Daoyuan Huang Bin Zhang Yuesheng Zuo Yingying Qin Guang-Hui Liu Yang Yu Jing Qu Si Wang Advanced Innovation center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational medicine center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative medicine Beijing 100101China CAS Key Laboratory of Genomic and Precision medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Institute for Stem cell and Regeneration CASBeijing 100101China China National center for Bioinformation Beijing 100101China The Fifth People’s Hospital of Chongqing Chongqing 400062China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish center for Education and Research Beijing 101408China Department of Obstetrics and Gynecology Center for Reproductive MedicinePeking UniversityThird HospitalBeijing 100191China Clinical Stem Cell Research center Peking UniversityThird HospitalBeijing 100191China center for reproductive medicine Cheeloo College of MedicineShandong UniversityJinan 250012China Key Laboratory of reproductive Endocrinology of Ministry of Education National Research Center for Assisted Reproductive Technology and Reproductive GeneticsShandong Key Laboratory of Reproductive MedicineShandong Provincial Clinical Research Center for Reproductive HealthJinan 250012China Key Laboratory of Organ Regeneration and Reconstruction Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Biomarker Consortium Beijing 100101China

The ovary is indispensable for female reproduction,and its age-dependent functional decline is the primary cause of ***,the molecular basis of ovarian aging in higher vertebrates remains poorly ***,we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate *** a global view,somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region,likely constituting a hostile microenvironment that facilitates ovarian ***,we uncovered that inflammation,the senescent-associated secretory phenotype,senescence,and fibrosis are the likely primary contributors to ovarian aging(PCOA).Of note,we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2(Metallothionein 2)highly expressing spot(MT2^(high))characterized by high levels of inflammation,potentially serving as an aging hotspot in the primate ***,with advanced age,a subpopulation of MT2^(high)accumulates,likely disseminating and amplifying the senescent signal *** study establishes the first primate spatiotemporal transcriptomic atlas,advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

关键词： spatial transcriptome primate ovary aging senescence inflammation

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Identification of two compound heterozygous GNRHR mutations in two siblings with congenital hypogonadotropic hypogonadism

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Asian Journal of Andrology 2024年第1期26卷 120-122页

作者： Xiao-Bin Wang Ping Chen Xue-Er Yu Zu-Liang Yao Ting-Chao Guo Bo-Chen Pan center for reproductive medicine Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyang 110004China NuProbe Shanghai 200433China Urology Surgery of The Affiliated reproductive Hospital of China Medical University and Liaoning Key Laboratory of reproductive Health Liaoning Research Institute of Family Planning(The Affiliated Reproductive Hospital of China Medical University)Shenyang 110031China NHC Key Laboratory of reproductive Health and Medical Genetics China Medical UniversityShenyang 110122China

DearEditor,Congenital hypogonadotropic hypogonadism(CHH)is a rare genetic disease characterized by gonadotropin-releasing hormone(GnRH)deficiency or insufficiency and normal hypothalamic-pituitary structures,resulting in defective sexual maturation or/and infertility.!CHH presents as a variety of nonreproductive phenotypes,such as renal hypoplasia,dental hypoplasia,or oculomotor abnormalities.

关键词： pogon compound ism

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RNF187 governs the maintenance of mouse GC-2 cell development by facilitating histone H3 ubiquitination at K57/80

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Asian Journal of Andrology 2024年第3期26卷 272-281页

作者： Bing-Ya Xu Xiang-Ling Yu Wen-Xin Gao Ting-Ting Gao Hao-Yue Hu Tian-Tian Wu Cong Shen Xiao-Yan Huang Bo Zheng Yi-Bo Wu Human reproductive and Genetic center Affiliated Hospital of Jiangnan UniversityWuxi 214122China State Key Laboratory of reproductive medicine Department of Histology and EmbryologySchool of Basic Medical SciencesNanjing Medical UniversityNanjing 211166China Changzhou Maternal and Child Health Care Hospital Changzhou Medical CenterNanjing Medical UniversityChangzhou 213000China State Key Laboratory of reproductive medicine Center for Reproduction and GeneticsSuzhou Municipal HospitalThe Affiliated Suzhou Hospital of Nanjing Medical UniversityGusu SchoolNanjing Medical UniversitySuzhou 215002China

RING finger 187(RNF187),a ubiquitin-ligating(E3)enzyme,plays a crucial role in the proliferation of cancer ***,it remains unclear whether RNF187 exhibits comparable functionality in the development of germline *** investigate thepotential involvement of RNF187 in germ cell development,we conducted interference and overexpression assays using GC-2 cells,a mouse spermatocyte-derived cell *** findings reveal that the interaction between RNF187 and histone H3 increases theviability,proliferation,and migratory capacity of GC-2 ***,we provide evidence demonstrating that RNF187 interactswith H3 and mediates the ubiquitination of H3 at lysine 57(K57)or lysine 80(K80),directly or indirectly resulting in increasedcellular *** is a study to report the role of RNF187 in maintaining the development of GC-2 cells by mediatinghistone H3 ubiquitination,thus highlighting the involvement of the K57 and K80 residues of H3 in the epistatic regulation of *** discoveries provide a new theoretical foundation for further comprehensive investigations into the functionof RNF187 in the reproductive system.

关键词： GC-2 cell histone H3 RNF187 ubiquitination

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Male reproductive function before and after the adjustment of the COVID-19 prevention policy:a multicenter study in China

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Asian Journal of Andrology 2024年第3期26卷 308-314页

作者： Jian-Zheng Li Han Wu Li Wang Yun-Shan Wang Feng Kong Long-Qiao Cao Ming Liang Xiong Wang Ming-Zhen Yuan Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan 250000China Institute of Women Children and Reproductive HealthShandong UniversityJinan 250012China Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province Jinan 250000China The First People’sHospital of Jining Jining 272000China Department of reproductive medicine The Second Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan 250000China reproductive medicine center Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantai 264000China

At the end of 2022,the adjustment of the coronavirus disease 2019(COVID-19)pandemic control policy in China resulted in alarge-scale increase in public *** compare the fertility parameters of male patients before and after the adjustments ofthe COVID-19 pandemic control policy in China,we collected data on patients’medical histories and laboratory examinations ontheir first visits between June 2022 and March 2023 in five different *** were divided into five groups according tothe timeline of the policy *** data we collected from male patients included semen quality and serum reproductivehormone levels,and intergroup comparisons were made using the Mann–Whitney U and Chi-square *** total,16784 casesunderwent regular semen analysis,11180 had sperm morphology assessments,and 7200 had reproductive hormone *** showed declining trends in semen volume,sperm motility,and the progressive sperm motility rate after the policy *** comparison revealed an initial decrease and gradual recovery in progressive motility *** morphology analysisshowed increased neck and tail abnormalities after the policy *** significant change in hormone levels was *** the adjustment of the COVID-19 prevention policy in China,a decline in sperm motility and morphology was *** trend may gradually recover over 2 *** the policy adjustment,reproductive hormone levels were relatively stablethroughout,except for an increase in luteinizing hormone(LH).These changes in semen parameters suggest that the policyadjustment had a short-to medium-term impact on male reproductive function.

关键词： COVID-19 multicenter study reproduction SARS-CoV-2 semen analysis

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Innovative insights into extrachromosomal circular DNAs in gynecologic tumors and reproduction

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Protein & Cell 2024年第1期15卷 6-20页

作者： Ning Wu Ling Wei Zhipeng Zhu Qiang Liu Kailong Li Fengbiao Mao Jie Qiao Xiaolu Zhao State Key Laboratory of Female Fertility Promotion Center for Reproductive MedicineDepartment of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijing 100191China National Clinical Research center for Obstetrics and Gynecology Peking University Third HospitalBeijing 100191China Key Laboratory of Assisted Reproduction(Peking University) Ministry of EducationBeijing 100191China Beijing Key Laboratory of reproductive Endocrinology and Assisted reproductive Technology Beijing 100191China Institute of Medical Innovation and Research Peking University Third HospitalBeijing 100191China Cancer center Peking University Third HospitalBeijing 100191China Department of Biochemistry and Biophysics Beijing Key Laboratory of Protein Posttranslational Modifications and Cell FunctionSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Beijing Advanced Innovation center for Genomics Beijing 100191China Peking-Tsinghua center for Life Sciences Peking UniversityBeijing 100191China

Originating but free from chromosomal DNA,extrachromosomal circular DNAs(eccDNAs)are organized in circular form and have long been found in unicellular and multicellular *** biogenesis and function are poorly understood as they are characterized by sequence homology with linear DNA,for which few detection methods are *** advances in high-throughput sequencing technologies have revealed that eccDNAs play crucial roles in tumor formation,evolution,and drug resistance as well as aging,genomic diversity,and other biological processes,bringing it back to the research *** mechanisms of eccDNA formation have been proposed,including the breakage-fusion-bridge(BFB)and translocation-deletion-amplification *** tumors and disorders of embryonic and fetal development are major threats to human reproductive *** roles of eccDNAs in these pathological processes have been partially elucidated since the first discovery of eccDNA in pig sperm and the double minutes in ovarian cancer *** present review summarized the research history,biogenesis,and currently available detection and analytical methods for eccDNAs and clarified their functions in gynecologic tumors and *** also proposed the application of eccDNAs as drug targets and liquid biopsy markers for prenatal diagnosis and the early detection,prognosis,and treatment of gynecologic *** review lays theoretical foundations for future investigations into the complex regulatory networks of eccDNAs in vital physiological and pathological processes.

关键词： extrachromosomal circular DNAs gynecologic tumors reproduction liquid biopsy non-invasive prena-tal testing

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GametesOmics:A Comprehensive Multi-omics Database for Exploring the Gametogenesis in Humans and Mice

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Genomics, Proteomics & Bioinformatics 2024年第1期22卷 121-130页

作者： Jianting An Jing Wang Siming Kong Shi Song Wei Chen Peng Yuan Qilong He Yidong Chen Ye Li Yi Yang Wei Wang Rong Li Liying Yan Zhiqiang Yan Jie Qiao State Key Laboratory of Female Fertility Promotion Center for Reproductive MedicineDepartment of Obstetrics and GynecologyPeking University Third HospitalBeijing 100191China National Clinical Research center for Obstetrics and Gynecology Peking University Third HospitalBeijing 100191China Key Laboratory of Assisted Reproduction Ministry of EducationPeking UniversityBeijing 100191China Beijing Key Laboratory of reproductive Endocrinology and Assisted reproductive Technology Beijing 100191China Peking-Tsinghua center for Life Sciences Peking UniversityBeijing 100871China Beijing Advanced Innovation center for Genomics Beijing 100191China

Gametogenesis plays an important role in the reproduction and evolution of *** transcriptomic and epigenetic alterations in this process can influence the reproductive capacity,fertilization,and embryonic *** rapidly increasing single-cell studies have provided valuable multi-omics ***,data from different layers and sequencing platforms have not been uniformed and integrated,which greatly limits their use for exploring the molecular mechanisms that underlie oogenesis and ***,we develop GametesOmics,a comprehensive database that integrates the data of gene expression,DNA methylation,and chromatin accessibility during oogenesis and spermatogenesis in humans and *** provides a user-friendly website and various tools,including Search and Advanced Search for querying the expression and epigenetic modification(s)of each gene;Tools with Differentially expressed gene(DEG)analysis for identifying DEGs,Correlation analysis for demonstrating the genetic and epigenetic changes,Visualization for displaying single-cell clusters and screening marker genes as well as master transcription factors(TFs),and MethylView for studying the genomic distribution of epigenetic *** also provides Genome Browser and Ortholog for tracking and comparing gene expression,DNA methylation,and chromatin accessibility between humans and *** offers a comprehensive resource for biologists and clinicians to decipher the cell fate transition in germ cell development,and can be accessed at http://***/.

关键词： Gametogenesis Oogenesis Spermatogenesis Transcriptomics Epigenomics

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Correction of a CADASIL point mutation using adenine base editors in hiPsCsandbloodvessel organoids

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Journal of Genetics and Genomics 2024年第2期51卷 197-207页

作者： Jingwen Wang Lei Zhang Guanglan Wu Jinni Wu Xinyao Zhou Xiaolin Chen Yongxia Niu Yiren Jiao Qianyi Liu Puping Liang Guang Shi Xueqing Wu Junjiu Huang MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China Key Laboratory of reproductive medicine of Guangdong Province The First Affiliated Hospital and School of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China center of reproductive medicine Children's Hospital of Shanxi and Women Health Center of ShanxiTaiyuanShanxi 030013China

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small vessel disease caused by mutations in the NOTCH3 gene. However, the pathogenesis of CADASIL remains unclear, and patients have limited treatment options. Here, we use human induced pluripotent stem cells (hiPSCs) generated from the peripheral blood mononuclear cells of a patient with CADASIL carrying a heterozygous NOTCH3 mutation (c.1261C>T, p.R421C) to develop a disease model. The correction efficiency of different adenine base editors (ABEs) is tested using the HEK293T-NOTCH3 reporter cell line. ABEmax is selected based on its higher efficiency and minimization of predicted off-target effects. Vascular smooth muscle cells (VSMCs) differentiated from CADASIL hiPSCs show NOTCH3 deposition and abnormal actin cytoskeleton structure, and the abnormalities are recovered in corrected hiPSC-derived VSMCs. Furthermore, CADASIL blood vessel organoids generated for in vivo modeling show altered expression of genes related to disease phenotypes, including the downregulation of cell adhesion, extracellular matrix organization, and vessel development. The dual adeno-associated virus (AAV) split-ABEmax system is applied to the genome editing of vascular organoids with an average editing efficiency of 8.82%. Collectively, we present potential genetic therapeutic strategies for patients with CADASIL using blood vessel organoids and the dual AAV split-ABEmax system.

关键词： CADASIL Induced pluripotent stem cells Adenine base editors AAV Blood vessel Organoid

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Emerging mechanisms and implications of c GAS-STING signaling in cancer immunotherapy strategies

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Cancer Biology & medicine 2024年第1期21卷 45-64页

作者： Jiawen Zhang Sihui Yu Qiao Peng Ping Wang Lan Fang Tongji University Cancer center Shanghai Tenth People’s HospitalSchool of MedicineTongji UniversityShanghai 200072China reproductive medicine center Department of Obstetrics and GynecologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 201620China Department of Obstetrics and Gynecology Zhongshan HospitalFudan UniversityShanghai 200032China

The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer *** this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key *** cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor ***,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer *** strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint *** approaches have shown promise in preclinical and clinical settings,by enhancing patient survival *** review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and ***,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy *** challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.

关键词： cGAS-STING pathway type I interferon cyclic dinucleotide STING agonist cancer immunotherapy

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scRNA-seq reveals that origin recognition complex subunit 6 regulates mouse spermatogonial cell proliferation and apoptosis via activation of Wnt/β-catenin signaling

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Asian Journal of Andrology 2024年第1期26卷 46-56页

作者： Shi-Wei Liu Jia-Qiang Luo Liang-Yu Zhao Ning-Jing Ou Chao-Yang Yu-Xiang Zhang Hao-Wei Bai Hong-Fang Sun Jian-Xiong Zhang Chen-Cheng Yao Peng Li Ru-Hui Tian Zheng Li Zi-Jue Zhu Department of Andrology Center for Men's HealthUrologic Medical CenterShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China State Key Lab of reproductive medicine Nanjing Medical UniversityNanjing 211166China Shanghai Key Lab of reproductive medicine Shanghai Jiao Tong University School of MedicineShanghai 200080China Department of Urology Guangdong Provincial Key Laboratory of Biomedical ImagingThe Fifth Affiliated HospitalSun Yat-sen UniversityZhuhai 519000China Department of Urology First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China

The regulation of spermatogonial proliferation and apoptosis is of great significance for maintaining *** single-cell RNA sequencing(scRNA-seq)analysis of the testis was performed to identify genes upregulated in *** scRNAseq analysis,we identified the spermatogonia upregulated gene origin recognition complex subunit 6(Orc6),which is involved in DNA replication and cell cycle regulation;its protein expression in the human and mouse testis was detected by western blot and *** explore the potential function of Orc6 in spermatogonia,the C18-4 cell line was transfected with control or Orc6 ***,5-ethynyl-2-deoxyuridine(EdU)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,flow cytometry,and western blot were used to evaluate its effects on proliferation and *** was revealed that ORC6 could promote proliferation and inhibit apoptosis of C18-4 *** RNA sequencing and bioinformatics analysis indicated that Orc6 was involved in the activation of wingless/integrated(Wnt)/β-catenin *** blot revealed that the expression ofβ-catenin protein and its phosphorylation(Ser675)were significantly decreased when silencing the expression of *** findings indicated that Orc6 was upregulated in spermatogonia,whereby it regulated proliferation and apoptosis by activating Wnt/β-catenin signaling.

关键词： cell proliferation ORCG scRNA-seq analysis spermatogonia Wnt/β-catenin signaling

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