Biology of Reproduction最新文献

{"title":"Deletion of an evolutionarily conserved TAD boundary impacts spermatogenesis in mice†.","authors":"Ana C Lima, Mariam Okhovat, Alexandra M Stendahl, Ran Yang, Jake VanCampen, Kimberly A Nevonen, Jarod Herrera, Weiyu Li, Lana Harshman, Lev M Fedorov, Katinka A Vigh-Conrad, Nadav Ahituv, Donald F Conrad, Lucia Carbone","doi":"10.1093/biolre/ioaf017","DOIUrl":"10.1093/biolre/ioaf017","url":null,"abstract":"<p><p>Spermatogenesis is a complex process that can be disrupted by genetic and epigenetic changes, potentially leading to male infertility. Recent research has rapidly increased the number of protein coding mutations causally linked to impaired spermatogenesis in humans and mice. However, the role of non-coding mutations remains largely unexplored. As a case study to evaluate the effects of non-coding mutations on spermatogenesis, we first identified an evolutionarily conserved topologically associated domain (TAD) boundary near two genes with important roles in mammalian testis function: Dmrtb1 and Lrp8. We then used CRISPR-Cas9 to generate a mouse line where 26 kb of the boundary was removed including a strong and evolutionarily conserved CTCF binding site. ChIP-seq and Hi-C experiments confirmed the removal of the CTCF site and a resulting mild increase in the DNA-DNA interactions across the domain boundary. Mutant mice displayed significant changes in testis gene expression, higher frequency of histological abnormalities, a drop of 47-52% in efficiency of meiosis, a 15-18% reduction in efficiency of spermatogenesis, and consistently, a 12-28% decrease in daily sperm production compared to littermate controls. Despite these quantitative changes in testis function, mutant mice show no significant changes in fertility. This suggests that non-coding deletions affecting testis gene regulation may have smaller effects on fertility compared to coding mutations of the same genes. Our results demonstrate that disruption of a TAD boundary can have a negative impact on sperm production and highlight the importance of considering non-coding mutations in the analysis of patients with male infertility.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187996","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":"Correction to: Roles of histone post-translational modifications in meiosis.","authors":"","doi":"10.1093/biolre/ioaf024","DOIUrl":"https://doi.org/10.1093/biolre/ioaf024","url":null,"abstract":"","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078598","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":"SHP2 regulates the HIF-1 signaling pathway in the decidual human endometrial stromal cells.","authors":"Liqun Ouyang, Xia Gao, Rongyu Yang, Peiyi Zhou, Han Cai, Yingpu Tian, Haibin Wang, Shuangbo Kong, Zhongxian Lu","doi":"10.1093/biolre/ioaf019","DOIUrl":"https://doi.org/10.1093/biolre/ioaf019","url":null,"abstract":"<p><p>The decidual endometrial stromal cells play a critical role in the establishment of uterine receptivity and pregnancy in human. Our previous studies demonstrate that protein tyrosine phosphatase 2 SHP2 is highly expressed in decidualized cells and governs the decidualization progress. However, the role and mechanism of SHP2 in the function of decidual cells remain unclear. Here, we screened proteins interacting with SHP2 in decidual hTERT-immortalized human endometrial stromal cells (T-HESCs) and identified Hypoxia-inducible factor-1 (HIF-1) signaling pathway as a potential SHP2-mediated signaling pathway through proximity-dependent biotinylation (BioID) analysis. Immunoprecipitation (Co-IP) revealed an interaction between SHP2 and HIF-1α, which colocalized to the nucleus in decidual cells. Furthermore, the SHP2 expression correlated with the transcriptional activation of HIF-1α and its downstream genes Beta-enolase (Eno3), Pyruvate kinase 2 (Pkm2), Aldolase C (Aldoc), and Facilitative glucose transporter 1 (Glut1). Knockdown or inhibition of SHP2 significantly reduced the mRNA and protein levels of HIF-1α and its downstream genes, as well as lactate production in decidual cells. We also established a hypoxia model of T-HESCs and 293T cells and found that hypoxic treatment induced the expression of SHP2 and HIF-1α, which colocalized in the nucleus. SHP2 forced-expression rescued the inhibitory effects of SHP2 deficiency on HIF-1α expression and lactate production. Finally, SHP2 binds to the promoter regions of HIF-1α and its target genes (Eno3, Pkm2, Aldoc, and Glut1). Collectively, our results suggest that SHP2 influences the function of decidual cells by HIF-1α signaling and provide a novel function mechanism of decidual stromal cells.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073664","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":"Roles of the EF-Hand Domain of PLCZ1 in Establishing Species-Specific Ca 2+ Oscillations in Mouse and Rat Fertilization†.","authors":"Hoi Chang Lee, Hiroki Akizawa, Rafael A Fissore","doi":"10.1093/biolre/ioaf021","DOIUrl":"https://doi.org/10.1093/biolre/ioaf021","url":null,"abstract":"<p><p>Periodic increases in cytosolic calcium concentration (Ca2+ oscillations) during mammalian fertilization induce all the events collectively known as egg activation. The sperm-specific phospholipase C, PLC zeta 1 (PLCZ1) represents the \"sperm factor\" vital for initiating the persistent Ca2+ oscillations in mammals. Despite sequence conservation, the Ca2+ oscillation-inducing properties of the enzyme differ vastly among species, and this is particularly salient between mouse and rat PLCZ1, where the activities vary at least one order of magnitude in favor of the former. As previously shown, injecting wild-type (WT) rat Plcz1 mRNA into metaphase II (MII) mouse eggs induced delayed Ca2+ oscillations with low specific activity compared to the homologous mouse Plcz1 mRNA. We, therefore, sought to uncover the factor(s) diversifying these enzymes by swapping functional domains between species, creating chimeric PLCZ1s. When injected into mouse MII eggs, mouse Plcz1 mRNA with the whole- or part of the EF-hand domains swapped with the rat showed a substantial reduction in activity compared to WT. Consistently, the opposite exchange enhanced the rat's enzyme activity. EF-hand domains 1 and 2 seemed to underlie most differences, and mutations of the divergent amino acids within these domains, substitutions for Glu(m-30; r-29) and Gln(m-58; r-57), changed the activity of both species' PLCZ1s in opposite directions. Collectively, our findings support the view that differences in the sequences of EF-hand domains, especially in several of its charged residues, underpin the distinct PLCZ1 activities between these species, revealing the gametes and species' adaptability to optimize the fertilization signal and early development.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073663","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":"METTL7A improves bovine IVF embryo competence by attenuating oxidative stress.","authors":"Linkai Zhu, Hao Ming, Giovanna N Scatolin, Andrew Xiao, Zongliang Jiang","doi":"10.1093/biolre/ioaf018","DOIUrl":"10.1093/biolre/ioaf018","url":null,"abstract":"<p><p>In vitro fertilization (IVF) is a widely used assisted reproductive technology to achieve a successful pregnancy. However, the acquisition of oxidative stress in embryo in vitro culture impairs its competence. Here, we demonstrated that a nuclear coding gene, methyltransferase-like protein 7A (METTL7A), improves the developmental potential of bovine embryos. We found that exogenous METTL7A modulates expression of genes involved in embryonic cell mitochondrial pathways and promotes trophectoderm development. Surprisingly, we discovered that METTL7A alleviates mitochondrial stress and DNA damage and promotes cell cycle progression during embryo cleavage. In summary, we have identified a novel mitochondria stress eliminating mechanism regulated by METTL7A that occurs during the acquisition of oxidative stress in embryo in vitro culture. This discovery lays the groundwork for the development of METTL7A as a promising therapeutic target for IVF embryo competence.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063496","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":"Effect of gestational age and fetal sex on metabolism of creatine by uteri, placentae, and fetuses of pigs†.","authors":"Nirvay Sah, Claire Stenhouse, Katherine M Halloran, Robyn M Moses, Makenzie G Newton, Heewon Seo, Joe W Cain, Carli M Lefevre, Gregory A Johnson, Guoyao Wu, Fuller W Bazer","doi":"10.1093/biolre/ioaf015","DOIUrl":"https://doi.org/10.1093/biolre/ioaf015","url":null,"abstract":"<p><p>The creatine (Cr) biosynthesis pathway buffers ATP in metabolically active tissues. We investigated whether sex of fetus and day of gestation influence Cr in endometrial and conceptus tissues from gilts on Days 60 and Day 90 (n = 6 gilts/day) of gestation. Uterine and conceptus tissues associated with one male and one female fetus from each gilt were analyzed for creatine, mRNAs, and proteins for Cr biosynthesis. Total Cr decreased in amniotic fluid but increased in allantoic fluid between Days 60 and 90 of gestation for male (P < 0.05), but not for female fetuses (P > 0.05). Endometrial expression of CKM, CKMT1, and SLC6A8 mRNAs increased (P < 0.05) between Days 60 and 90 only for female fetuses. On Day 60, expression of CKB and CKMT1 mRNAs was greater (P < 0.05) for placentae of female than male fetuses. Livers of male fetuses had greater expression of AGAT and CKB than for females on Day 60, while kidneys of female fetuses had greater expression of GAMT than male fetuses on Day 90 (P < 0.05). Localization of GAMT, CKB, CKMT1 and SLC6A8 proteins to uterine and chorionic epithelium was not influenced by gestational age or fetal sex. AGAT localized to fetal kidneys and appeared greater on Day 90 than Day 60 in both sexes. Thus, expression of the creatine-creatine kinase-phosphocreatine (Cr-CK-PCr) system at the uterine-conceptus interface is affected by gestational age and fetal sex to influence energy homeostasis in pigs.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999561","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":"Collagen turnover during cervical remodeling involves both intracellular and extracellular collagen degradation pathways.","authors":"Mariano Colon-Caraballo, Serena R Russell, Kristin M Myers, Mala Mahendroo","doi":"10.1093/biolre/ioaf012","DOIUrl":"https://doi.org/10.1093/biolre/ioaf012","url":null,"abstract":"<p><p>Reproductive success requires accurately timed remodeling of the cervix to orchestrate the maintenance of pregnancy, the process of labor, and birth. Prior work in mice established that a combination of continuous turnover of fibrillar collagen and reduced formation of collagen cross-links allows for the gradual increase in tissue compliance and delivery of the fetus during labor. However, the mechanism for continuous collagen degradation to ensure turnover during cervical remodeling is still unknown. This study demonstrates the functional role of extracellular and intracellular collagen degradative pathways in two different settings of cervical remodeling: physiological term remodeling and inflammation-mediated premature remodeling. Extracellular collagen degradation is achieved by the activity of fibroblast-derived matrix metalloproteases MMP14, MMP2, and fibroblast activation protein (FAP). In parallel, we demonstrate the function of an intracellular collagen degradative pathway in fibroblast cells mediated by the collagen endocytic mannose receptor type-2 (MRC2). These pathways appear to be functionally redundant as loss of MRC2 does not obstruct collagen turnover or cervical function in pregnancy. While both extracellular and intracellular pathways are also utilized in inflammation-mediated premature cervical remodeling, the extracellular collagen degradation pathway uniquely employs fibroblast and immune-cell derived proteases. In sum, these findings identify the dual utilization of two distinct degradative pathways as a failsafe mechanism to achieve continuous collagen turnover in the cervix, thereby allowing dynamic shifts in cervical tissue mechanics and function.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999560","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":"Effect of introducing somatic mitochondria into an early embryo on zygotic gene activation†.","authors":"Yoshihiro Hayashi, Hanako Bai, Masashi Takahashi, Tomohiro Mitani, Manabu Kawahara","doi":"10.1093/biolre/ioaf010","DOIUrl":"https://doi.org/10.1093/biolre/ioaf010","url":null,"abstract":"<p><p>Unlike differentiated somatic cells, which possess elongated mitochondria, undifferentiated cells, such as those of preimplantation embryos, possess round, immature mitochondria. Mitochondrial morphology changes dynamically during cell differentiation in a process called mitochondrial maturation. The significance of the alignment between cell differentiation and mitochondrial maturity in preimplantation development remains unclear. In this study, we analyzed mouse embryos into which liver-derived somatic mitochondria were introduced (SM-embryos). Most SM-embryos were arrested at the two-cell stage. Some of the introduced somatic mitochondria became round, while others remained elongated and large. RNA-sequencing revealed a disruption of both minor and major zygotic gene activation (ZGA) in SM-embryos. Minor ZGA did not terminate before major ZGA, and the onset of major ZGA was inhibited, as shown by histone modification analyses of histone H3 lysine 4 trimethylation and histone H3 lysine 27 acetylation. Further analysis of metabolites involved in histone modification regulation in SM-embryos showed a significantly lower NAD+/NADH ratio in SM-embryos than in control embryos. Additionally, the mitochondrial membrane potential, an indicator of mitochondrial function, was lower in SM-embryos than in control embryos. Our results demonstrated that introducing somatic mitochondria into an embryo induces mitochondrial dysfunction, thereby disrupting metabolite production, leading to a disruption in ZGA and inducing developmental arrest. Our findings reveal that the alignment between cell differentiation and mitochondrial maturity is essential for early embryonic development.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982595","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":"Small extracellular vesicles derived from the crosstalk between early embryos and the endometrium potentially mediate corpus luteum function†.","authors":"Alessandra Bridi, Juliano Rodrigues Sangalli, Ricardo Perecin Nociti, Angélica Camargo Dos Santos, Luana Alves, Natália Marins Bastos, Giuliana de Ávila Ferronato, Paola Maria da Silva Rosa, Mariani Farias Fiorenza, Guilherme Pugliesi, Flávio Vieira Meirelles, Marcos Roberto Chiaratti, Juliano Coelho da Silveira, Felipe Perecin","doi":"10.1093/biolre/ioae143","DOIUrl":"10.1093/biolre/ioae143","url":null,"abstract":"<p><p>The first interactions among the embryo, endometrium, and corpus luteum are essential for pregnancy success. Small extracellular vesicles (sEVs) are part of these interactions. We previously demonstrated that small extracellular vesicles from in vivo- or in vitro-produced bovine embryos contain different miRNA cargos. Herein we show: (1) the presence and origin (in vivo or in vitro) of the blastocyst differentially reprograms endometrial transcriptional profiles; (2) the endometrial explant (EE) cultured with in vivo or in vitro embryos release small extracellular vesicles with different miRNA contents, and (3) the luteal explant (CLE) exposed to these small extracellular vesicles have distinct mRNA and miRNA profiles. To elucidate this, the endometrial explant were cultured in the presence or absence of a single Day-7 in vivo (EE-artificial insemination; EE-AI) or in vitro (EE-in vitro fertilization; EE-IVF) embryo. After of culture we found, in the endometrial explant, 45 and 211 differentially expressed genes associated with embryo presence and origin, respectively. Small extracellular vesicles were recovered from the conditioned media (CM) in which endometrial explant and embryos were co-cultured. Four miRNAs were differentially expressed between small extracellular vesicles from CC-EE-AI and CC-EE-IVF. Luteal explants exposed in culture to these small extracellular vesicles showed 1360 transcripts and 15 miRNAs differentially expressed. The differentially expressed genes associated with embryo presence and origin, modulating cells' proliferation, and survival. These results demonstrate that in vivo- or in vitro-produced bovine embryos induce molecular alterations in the endometrium; and that the embryo and endometrium release small extracellular vesicles capable of modifying the messenger RNA (mRNA) and miRNA profile in the corpus luteum. Therefore, the small extracellular vesicles-mediated embryo-endometrium-corpus luteum interactions possibly regulate the corpus luteum viability to ensure pregnancy success.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"54-69"},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457240","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":"Roe deer uterine fluid metabolome reveals elevated glycolysis, fatty acid breakdown, and spermidine synthesis upon reactivation from diapause†.","authors":"Sara Elsafadi, Anna-Katharina Hankele, Pieter Giesbertz, Susanne E Ulbrich","doi":"10.1093/biolre/ioae161","DOIUrl":"10.1093/biolre/ioae161","url":null,"abstract":"<p><p>The blastocyst of the European roe deer (Capreolus capreolus) undergoes a period of decelerated growth and limited metabolism. During this period known as embryonic diapause, it floats freely in the uterus encircled by the histotroph. Prior to implantation, reactivation is marked by rapid embryonic growth and conceptus elongation. We hypothesized that the uterine fluid, which is known to undergo changes in its composition to support early embryonic development, contributes to controlling embryonic growth during diapause and elongation. We therefore characterized the pre-implantation uterine fluid metabolome during diapause and at elongation by mass spectrometry and particularly assessed nonpolar lipids, polar metabolites, acylcarnitines, and polyamines. Our results show that triglycerides and diglycerides levels decreased at elongation, likely serving as a source for membrane synthesis rather than for energy production. A functional analysis identified glycolysis as a key pathway during elongation, which may compensate for the energy requirements during this phase. We also observed an increase of sphingomyelin; prostaglandin precursors; and the amino acids asparagine, glutamine, and methionine upon elongation. The sphingolipid and glycerophospholipid metabolism pathways were implicated during elongation. Particularly, spermidine, and to some extent spermine but not putrescine-levels significantly increased in the uterine fluid during elongation, indicating their significance for reactivation and/or proliferation at embryo elongation. We conclude that the roe deer uterine fluid sustained dynamic compositional changes necessary to support the energy- and resource-intensive conceptus elongation. However, it remains to be determined whether these changes are the cause or a consequence of embryo elongation. Studying the metabolic changes and molecular interactions in the roe deer during diapause and elongation not only reveals insights into aspects of its reproductive strategy, but also deepens our knowledge of embryo metabolic demands and developmental velocities across species.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"70-85"},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823860","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}