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Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 15615

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Prof. Dr. Sergio Minucci

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Dipartimento di Medicina Sperimentale, Sez. Fisiologia Umana e Funzioni Biologiche Integrate, Università degli Studi della Campania ‘Luigi Vanvitelli’, Via Santa Maria di Costantinopoli, 16-80138 Napoli, Italy
Interests: reproduction; spermatogenesis; reproductive toxicology; apoptosis; testicular cytoskeleton; gene expression; fertility
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Dear Colleagues,

The reproductive activity of a species is crucial to ensure its survival and genetic variability. Therefore, the production and differentiation of good-quality gametes, which are capable of fertilizing or being fertilized, is of primary importance. In contrast, there is a worrying decline in fertility worldwide, directly proportional to the increased worsening in gametes quality. Thus, studies on the molecular mechanisms that regulate male and female gametogenesis are encouraged, not only to add new knowledge on the biological aspects of these differentiative processes, but also to identify new potential markers of proper fertility and/or therapeutic targets on which to act to improve it.

This Special Issue aims to cover the physiological and pathological aspects of gamete production and differentiation, at the histological, cellular, and biomolecular levels. This incorporates but is not limited to all aspects related to gamete function, including sperm and oocyte maturation, epididymal transit, fertilization, sperm motility, capacitation, and acrosome reaction. Papers focusing on the influence of environmental pollutants (endocrine disrupting chemicals, microplastics, etc.) on gametes are also welcome. Papers on any vertebrate (including human) and non-vertebrate species will be accepted, as well as in vitro and ex vivo studies.

This Special Issue welcomes research articles, case reports, short communications, letters, and review articles.

Prof. Dr. Sergio Minucci
Guest Editor

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Keywords

spermatogenesis
oogenesis
spermatozoa
oocyte
fertilization
acrosome reaction
fertility
epidydimal transit
endocrine disrupting chemicals
testicular and ovarian cancer

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Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization, 2nd Edition in International Journal of Molecular Sciences (3 articles)

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Research

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14 pages, 3813 KiB

Open AccessArticle

FoxH1 Represses the Promoter Activity of cyp19a1a in the Ricefield Eel (Monopterus albus)

by Zhi He, Qiqi Chen, Jinxin Xiong, Mingqiang Chen, Kuo Gao, Bolin Lai, Wenxiang Ding, Junjie Huang, Li Zheng, Yong Pu, Ziting Tang, Mingwang Zhang, Deying Yang and Taiming Yan

Int. J. Mol. Sci. 2023, 24(18), 13712; https://doi.org/10.3390/ijms241813712 - 5 Sep 2023

Cited by 1 | Viewed by 1213

Abstract

Forkhead box H1 (FoxH1) is a sexually dimorphic gene in Oreochromis niloticus, Oplegnathus fasciatus, and Acanthopagrus latus, indicating that it is essential for gonadal development. In the present study, the molecular characteristics and potential function of FoxH1 and the activation of the cyp19a1a promoter in vitro were evaluated in Monopterus albus. The levels of foxh1 in the ovaries were three times higher than those in the testes and were regulated by gonadotropins (Follicle-Stimulating Hormone and Human Chorionic Gonadotropin). FoxH1 colocalized with Cyp19a1a in the oocytes and granulosa cells of middle and late vitellogenic follicles. In addition, three FoxH1 binding sites were identified in the proximal promoter of cyp19a1a, namely, FH1 (−871/−860), FH2 (−535/−524), and FH3 (−218/−207). FoxH1 overexpression significantly attenuated the activity of the cyp19a1a promoter in CHO cells, and FH1/2 mutation increased promoter activity. Taken together, these results suggest that FoxH1 may act as an important regulator in the ovarian development of M. albus by repressing cyp19a1a promoter activity, which provides a foundation for the study of FoxH1 function in bony fish reproductive processes. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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13 pages, 2210 KiB

Open AccessArticle

SUMO1 and Defective Spermatozoa Correlate with Endogenous Hydrogen Peroxide and Live Birth Outcome in Intrauterine Insemination Cycles for Unexplained Infertility

by Ming-Chao Huang, Shu-Ling Tzeng, Wen-Jung Chen, Sung-Lang Chen, You-Ren Ding, Chun-I Lee, Maw-Sheng Lee and Tsung-Hsien Lee

Int. J. Mol. Sci. 2023, 24(16), 12775; https://doi.org/10.3390/ijms241612775 - 14 Aug 2023

Cited by 1 | Viewed by 1127

Abstract

This study aimed to investigate the correlation between hydrogen peroxide (H₂O₂), small ubiquitin-like modifier molecules (SUMO), and pregnancy outcomes in couples with unexplained infertility (UI) undergoing intrauterine insemination (IUI) treatment. We prospectively collected semen samples from 56 couples with UI and divided the spermatozoa into motile and immotile fractions by density gradient centrifugation (DSC). Immunofluorescence staining was used to examine the immunostaining and localization of nuclear pore complex (NPC), SUMO1, and SUMO2/3 in spermatozoa. We detected H₂O₂ levels by chemiluminescence methods. We found that H₂O₂ levels correlated with NPC (neck) (r = 0.400) and NPC (tail) (r = 0.473) in motile sperm fractions. In immotile fractions, H₂O₂ positively correlated with NPC (tail) (r = 0.431) and SUMO1 (neck) (r = 0.282). Furthermore, the positive NPC (tail) group had a significantly lower live birth rate than the negative NPC group (17.9% = 5/28 vs. 42.9% = 12/28). In conclusion, H₂O₂ positively correlated with SUMO1 (neck) and NPC (tail) in human spermatozoa. The DSC may partially eliminate defective spermatozoa (positive NPC staining); however, if defective spermatozoa remain in the motile fraction, this scenario is associated with a low live birth rate following IUI treatment. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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10 pages, 1905 KiB

Open AccessArticle

Translocation of Oocytic HES1 into Surrounding Cumulus Cells in Bovine: Mechanism of Cellular Interaction during IVM?

by Ralf Pöhland, Jens Vanselow and Fabiana Melo Sterza

Int. J. Mol. Sci. 2023, 24(15), 11932; https://doi.org/10.3390/ijms241511932 - 25 Jul 2023

Viewed by 1133

Abstract

HES1 (hairy and enhancer of split-1, effector of the NOTCH pathway) plays a role in oocyte maturation and has been detected so far mainly in somatic follicular cells. In this study, we aimed to investigate whether HES1 is present in both compartments of bovine cumulus oocyte complexes (COCs) and whether in vitro maturation itself has an effect on its distribution. We investigated the abundance of HES1 mRNA and protein in bovine COCs characterized by Brilliant-Cresyl-Blue (BCB) stainability by RT-PCR and immunofluorescence before and after in vitro maturation (IVM). To study the interaction of the compartments and the possible translocation of HES1, we injected GFP-HES1 mRNA into oocytes before maturation and analyzed fluorescence recovery after photobleaching (FRAP). The results showed that HES1 mRNA was detectable in oocytes but not in cumulus cells. The number of transcripts increased with maturation, especially in BCB-positive oocytes. In contrast, the protein was mainly visible in cumulus cells both before and after maturation. After GFP-HES1-mRNA injection into oocytes, a signal could be detected not only in the oocytes but also in cumulus cells. Our result shows a nearly exclusive distribution of HES1 mRNA and protein in oocytes and cumulus cells, respectively, that might be explained by the transfer of the protein from the oocyte into cumulus cells. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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15 pages, 12297 KiB

Open AccessArticle

Comparative Transcriptome Profiling of CMS-D2 and CMS-D8 Systems Characterizes Fertility Restoration Genes Network in Upland Cotton

by Xiatong Song, Meng Zhang, Kashif Shahzad, Xuexian Zhang, Liping Guo, Tingxiang Qi, Huini Tang, Hailin Wang, Xiuqin Qiao, Juanjuan Feng, Yang Han, Chaozhu Xing and Jianyong Wu

Int. J. Mol. Sci. 2023, 24(13), 10759; https://doi.org/10.3390/ijms241310759 - 28 Jun 2023

Viewed by 1276

Abstract

Resolving the genetic basis of fertility restoration for cytoplasmic male sterility (CMS) can improve the efficiency of three-line hybrid breeding. However, the genetic determinants of male fertility restoration in cotton are still largely unknown. This study comprehensively compared the full-length transcripts of CMS-D2 and CMS-D8 systems to identify potential genes linked with fertility restorer genes Rf₁ or Rf₂. Target comparative analysis revealed a higher percentage of differential genes in each restorer line as compared to their corresponding sterile and maintainer lines. An array of genes with specific expression in the restorer line of CMS-D2 had functional annotations related to floral development and pathway enrichments in various secondary metabolites, while specifically expressed genes in the CMS-D8 restorer line showed functional annotations related to anther development and pathway enrichment in the biosynthesis of secondary metabolites. Further analysis identified potentially key genes located in the target region of fertility restorer genes Rf₁ or Rf₂. In particular, Ghir_D05G032450 can be the candidate gene related to restorer gene Rf₁, and Ghir_D05G035690 can be the candidate gene associated with restorer gene Rf₂. Further gene expression validation with qRT-PCR confirmed the accuracy of our results. Our findings provide useful insights into decoding the potential regulatory network that retrieves pollen fertility in cotton and will help to further reveal the differences in the genetic basis of fertility restoration for two CMS systems. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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27 pages, 8059 KiB

Open AccessArticle

A Million-Cow Genome-Wide Association Study of Three Fertility Traits in U.S. Holstein Cows

by Zuoxiang Liang, Dzianis Prakapenka, Paul M. VanRaden, Jicai Jiang, Li Ma and Yang Da

Int. J. Mol. Sci. 2023, 24(13), 10496; https://doi.org/10.3390/ijms241310496 - 22 Jun 2023

Cited by 9 | Viewed by 2680

Abstract

A genome-wide association study (GWAS) of the daughter pregnancy rate (DPR), cow conception rate (CCR), and heifer conception rate (HCR) using 1,001,374–1,194,736 first-lactation Holstein cows and 75,140–75,295 SNPs identified 7567, 3798, and 726 additive effects, as well as 22, 27, and 25 dominance effects for DPR, CCR, and HCR, respectively, with log₁₀(1/p) > 8. Most of these effects were new effects, and some new effects were in or near genes known to affect reproduction including GNRHR, SHBG, and ESR1, and a gene cluster of pregnancy-associated glycoproteins. The confirmed effects included those in or near the SLC4A4-GC-NPFFR2 and AFF1 regions of Chr06 and the KALRN region of Chr01. Eleven SNPs in the CEBPG-PEPD-CHST8 region of Chr18, the AFF1-KLHL8 region of Chr06, and the CCDC14-KALRN region of Chr01 with sharply negative allelic effects and dominance values for the recessive homozygous genotypes were recommended for heifer culling. Two SNPs in and near the AGMO region of Chr04 that were sharply negative for HCR and age at first calving, but slightly positive for the yield traits could also be considered for heifer culling. The results from this study provided new evidence and understanding about the genetic variants and genome regions affecting the three fertility traits in U.S. Holstein cows. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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13 pages, 2285 KiB

Open AccessCommunication

Identification and Functional Analysis of foxo Genes in Chinese Tongue Sole (Cynoglossus semilaevis)

by Tingting Zhang, Mengqian Zhang, Yuxuan Sun, Lu Li, Peng Cheng, Xihong Li, Na Wang, Songlin Chen and Wenteng Xu

Int. J. Mol. Sci. 2023, 24(8), 7625; https://doi.org/10.3390/ijms24087625 - 21 Apr 2023

Cited by 1 | Viewed by 1717

Abstract

The Chinese tongue sole (Cynoglossus semilaevis) is a traditional, precious fish in China. Due to the large growth difference between males and females, the investigation of their sex determination and differentiation mechanisms receives a great deal of attention. Forkhead Box O (FoxO) plays versatile roles in the regulation of sex differentiation and reproduction. Our recent transcriptomic analysis has shown that foxo genes may participate in the male differentiation and spermatogenesis of Chinese tongue sole. In this study, six Csfoxo members (Csfoxo1a, Csfoxo3a, Csfoxo3b, Csfoxo4, Csfoxo6-like, and Csfoxo1a-like) were identified. Phylogenetic analysis indicated that these six members were clustered into four groups corresponding to their denomination. The expression patterns of the gonads at different developmental stages were further analyzed. All members showed high levels of expression in the early stages (before 6 months post-hatching), and this expression was male-biased. In addition, promoter analysis found that the addition of C/EBPα and c-Jun transcription factors enhanced the transcriptional activities of Csfoxo1a, Csfoxo3a, Csfoxo3b, and Csfoxo4. The siRNA-mediated knockdown of the Csfoxo1a, Csfoxo3a, and Csfoxo3b genes in the testicular cell line of Chinese tongue sole affected the expression of genes related to sex differentiation and spermatogenesis. These results have broadened the understanding of foxo’s function and provide valuable data for studying the male differentiation of tongue sole. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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24 pages, 2833 KiB

Open AccessArticle

Mitochondrial DNA Supplementation of Oocytes Has Downstream Effects on the Transcriptional Profiles of Sus scrofa Adult Tissues with High mtDNA Copy Number

by Takashi Okada, Alexander Penn and Justin C. St. John

Int. J. Mol. Sci. 2023, 24(8), 7545; https://doi.org/10.3390/ijms24087545 - 19 Apr 2023

Cited by 1 | Viewed by 1719

Abstract

Oocytes can be supplemented with extra copies of mitochondrial DNA (mtDNA) to enhance developmental outcome. Pigs generated through supplementation with mtDNA derived from either sister (autologous) or third-party (heterologous) oocytes have been shown to exhibit only minor differences in growth, physiological and biochemical assessments, and health and well-being do not appear affected. However, it remains to be determined whether changes in gene expression identified during preimplantation development persisted and affected the gene expression of adult tissues indicative of high mtDNA copy number. It is also unknown if autologous and heterologous mtDNA supplementation resulted in different patterns of gene expression. Our transcriptome analyses revealed that genes involved in immune response and glyoxylate metabolism were commonly affected in brain, heart and liver tissues by mtDNA supplementation. The source of mtDNA influenced the expression of genes associated with oxidative phosphorylation (OXPHOS), suggesting a link between the use of third-party mtDNA and OXPHOS. We observed a significant difference in parental allele-specific imprinted gene expression in mtDNA-supplemented-derived pigs, with shifts to biallelic expression with no effect on expression levels. Overall, mtDNA supplementation influences the expression of genes in important biological processes in adult tissues. Consequently, it is important to determine the effect of these changes on animal development and health. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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15 pages, 3291 KiB

Open AccessArticle

Transfer of Galectin-3-Binding Protein via Epididymal Extracellular Vesicles Promotes Sperm Fertilizing Ability and Developmental Potential in the Domestic Cat Model

by Tricia Rowlison and Pierre Comizzoli

Int. J. Mol. Sci. 2023, 24(4), 3077; https://doi.org/10.3390/ijms24043077 - 4 Feb 2023

Cited by 1 | Viewed by 1783

Abstract

Key proteins transferred by epididymal extracellular vesicles (EVs) to the transiting sperm cells contribute to their centrosomal maturation and developmental potential. Although not reported in sperm cells yet, galectin-3-binding protein (LGALS3BP) is known to regulate centrosomal functions in somatic cells. Using the domestic cat model, the objectives of this study were to (1) detect the presence and characterize the transfer of LGALS3BP via EVs between the epididymis and the maturing sperm cells and (2) demonstrate the impact of LGALS3BP transfer on sperm fertilizing ability and developmental potential. Testicular tissues, epididymides, EVs, and spermatozoa were isolated from adult individuals. For the first time, this protein was detected in EVs secreted by the epididymal epithelium. The percentage of spermatozoa with LGALS3BP in the centrosome region increased as cells progressively incorporated EVs during the epididymal transit. When LGALS3BP was inhibited during in vitro fertilization with mature sperm cells, less fertilized oocytes and slower first cell cycles were observed. When the protein was inhibited in epididymal EVs prior to incubation with sperm cells, poor fertilization success further demonstrated the role of EVs in the transfer of LGALS3BP to the spermatozoa. The key roles of this protein could lead to new approaches to enhance or control fertility in clinical settings. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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Review

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22 pages, 3794 KiB

Open AccessReview

Novel Aspects of cAMP-Response Element Modulator (CREM) Role in Spermatogenesis and Male Fertility

by Diego Eduardo Sánchez-Jasso, Sergio Federico López-Guzmán, Rosa Maria Bermúdez-Cruz and Norma Oviedo

Int. J. Mol. Sci. 2023, 24(16), 12558; https://doi.org/10.3390/ijms241612558 - 8 Aug 2023

Cited by 5 | Viewed by 2094

Abstract

Spermatogenesis is a very complex process with an intricate transcriptional regulation. The transition from the diploid to the haploid state requires the involvement of specialized genes in meiosis, among other specific functions for the formation of the spermatozoon. The transcription factor cAMP-response element modulator (CREM) is a key modulator that triggers the differentiation of the germ cell into the spermatozoon through the modification of gene expression. CREM has multiple repressor and activator isoforms whose expression is tissue-cell-type specific and tightly regulated by various factors at the transcriptional, post-transcriptional and post-translational level. The activator isoform CREMτ controls the expression of several relevant genes in post-meiotic stages of spermatogenesis. In addition, exposure to xenobiotics negatively affects CREMτ expression, which is linked to male infertility. On the other hand, antioxidants could have a positive effect on CREMτ expression and improve sperm parameters in idiopathically infertile men. Therefore, CREM expression could be used as a biomarker to detect and even counteract male infertility. This review examines the importance of CREM as a transcription factor for sperm production and its relevance in male fertility, infertility and the response to environmental xenobiotics that may affect CREMτ expression and the downstream regulation that alters male fertility. Also, some health disorders in which CREM expression is altered are discussed. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization)

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