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19 pages, 4123 KiB

Open AccessArticle

Chemogenetic Depletion of Hypophysiotropic GnRH Neurons Does Not Affect Fertility in Mature Female Zebrafish

by Sakura Tanaka, Nilli Zmora, Berta Levavi-Sivan and Yonathan Zohar

Int. J. Mol. Sci. 2022, 23(10), 5596; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105596 - 17 May 2022

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The hypophysiotropic gonadotropin-releasing hormone (GnRH) and its neurons are crucial for vertebrate reproduction, primarily in regulating luteinizing hormone (LH) secretion and ovulation. However, in zebrafish, which lack GnRH1, and instead possess GnRH3 as the hypophysiotropic form, GnRH3 gene knockout did not affect reproduction. [...] Read more.

The hypophysiotropic gonadotropin-releasing hormone (GnRH) and its neurons are crucial for vertebrate reproduction, primarily in regulating luteinizing hormone (LH) secretion and ovulation. However, in zebrafish, which lack GnRH1, and instead possess GnRH3 as the hypophysiotropic form, GnRH3 gene knockout did not affect reproduction. However, early-stage ablation of all GnRH3 neurons causes infertility in females, implicating GnRH3 neurons, rather than GnRH3 peptides in female reproduction. To determine the role of GnRH3 neurons in the reproduction of adult females, a Tg(gnrh3:Gal4ff; UAS:nfsb-mCherry) line was generated to facilitate a chemogenetic conditional ablation of GnRH3 neurons. Following ablation, there was a reduction of preoptic area GnRH3 neurons by an average of 85.3%, which was associated with reduced pituitary projections and gnrh3 mRNA levels. However, plasma LH levels were unaffected, and the ablated females displayed normal reproductive capacity. There was no correlation between the number of remaining GnRH3 neurons and reproductive performance. Though it is possible that the few remaining GnRH3 neurons can still induce an LH surge, our findings are consistent with the idea that GnRH and its neurons are likely dispensable for LH surge in zebrafish. Altogether, our results resurrected questions regarding the functional homology of the hypophysiotropic GnRH1 and GnRH3 in controlling ovulation. Full article

(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)

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20 pages, 4180 KiB

Open AccessArticle

Novel Pituitary Actions of TAC4 Gene Products in Teleost

by Xuetao Shi, Cheng Ye, Xiangfeng Qin, Lingling Zhou, Chuanhui Xia, Tianyi Cai, Yunyi Xie, Zhan Yin and Guangfu Hu

Int. J. Mol. Sci. 2021, 22(23), 12893; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312893 - 29 Nov 2021

Cited by 3 | Viewed by 1981

Abstract

Tachykinin 4 (TAC4) is the latest member of the tachykinin family involved in several physiological functions in mammals. However, little information is available about TAC4 in teleost. In the present study, we firstly isolated TAC4 and six neurokinin receptors (NKRs) from grass carp [...] Read more.

Tachykinin 4 (TAC4) is the latest member of the tachykinin family involved in several physiological functions in mammals. However, little information is available about TAC4 in teleost. In the present study, we firstly isolated TAC4 and six neurokinin receptors (NKRs) from grass carp brain and pituitary. Sequence analysis showed that grass carp TAC4 could encode two mature peptides (namely hemokinin 1 (HK1) and hemokinin 2 (HK2)), in which HK2 retained the typical FXGLM motif in C-terminal of tachyinin, while HK1 contained a mutant VFGLM motif. The ligand-receptor selectivity showed that HK2 could activate all 6 NKRs but with the highest activity for the neurokinin receptor 2 (NK2R). Interestingly, HK1 displayed a very weak activation for each NKR isoform. In grass carp pituitary cells, HK2 could induce prolactin (PRL), somatolactin α (SLα), urotensin 1 (UTS1), neuromedin-B 1 (NMB1), cocaine- and amphetamine-regulated transcript 2 (CART2) mRNA expression mediated by NK2R and neurokinin receptor 3 (NK3R) via activation cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), phospholipase C (PLC)/inositol 1,4,5-triphosphate (IP3)/protein kinase C (PKC) and calcium²⁺ (Ca²⁺)/calmodulin (CaM)/calmodulin kinase-II (CaMK II) cascades. However, the corresponding stimulatory effects triggered by HK1 were found to be notably weaker. Furthermore, based on the structural base for HK1, our data suggested that a phenylalanine (F) to valine (V) substitution in the signature motif of HK1 might have contributed to its weak agonistic actions on NKRs and pituitary genes regulation. Full article

(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)

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21 pages, 7018 KiB

Open AccessArticle

Changes in Porcine Corpus Luteum Proteome Associated with Development, Maintenance, Regression, and Rescue during Estrous Cycle and Early Pregnancy

by Pawel Likszo, Dariusz Jan Skarzynski and Beenu Moza Jalali

Int. J. Mol. Sci. 2021, 22(21), 11740; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111740 - 29 Oct 2021

Cited by 6 | Viewed by 2141

Abstract

Corpus luteum (CL), a transitory gland, undergoes rapid growth in a limited time to produce progesterone (P4) followed by its regression. A complex molecular signaling is involved in controlling luteal P4 production. In the present study, 2D gel electrophoresis-based proteomics and in silico [...] Read more.

Corpus luteum (CL), a transitory gland, undergoes rapid growth in a limited time to produce progesterone (P4) followed by its regression. A complex molecular signaling is involved in controlling luteal P4 production. In the present study, 2D gel electrophoresis-based proteomics and in silico functional analysis were used to identify changes in key proteins and pathways in CL along the different stages of the estrous cycle as its development progresses from early (Day 3) to mid-luteal phase (Day 9), effective functioning (Day 12) followed by regression (Day 15) or, in the case of pregnancy, rescue of function (Day 15). A total of 273 proteins were identified by MALDI-MS/MS analysis that showed significant changes in abundances at different stages of CL development or regression and rescue. Functional annotation of differentially abundant proteins suggested enrichment of several important pathways and functions during CL development and function maintenance including cell survival, endocytosis, oxidative stress response, estradiol metabolism, and angiogenesis. On the other hand, differentially abundant proteins during CL regression were associated with decreased steroid synthesis and metabolism and increased apoptosis, necrosis, and infiltration of immune cells. Establishment of pregnancy rescues CL from regression by maintaining the expression of proteins that support steroidogenesis as pathways such as the super-pathway of cholesterol biosynthesis, RhoA signaling, and functions such as fatty acid metabolism and sterol transport were enriched in CL of pregnancy. In this study, some novel proteins were identified along CL development that advances our understanding of CL survival and steroidogenesis. Full article

(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)

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27 pages, 5835 KiB

Open AccessArticle

Transcriptome and Proteome Analysis Revealed Key Pathways Regulating Final Stage of Oocyte Maturation of the Turkey (Meleagris gallopavo)

by Mariola Słowińska, Łukasz Paukszto, Laura Pardyak, Jan P. Jastrzębski, Ewa Liszewska, Joanna Wiśniewska, Krzysztof Kozłowski, Jan Jankowski, Barbara Bilińska and Andrzej Ciereszko

Int. J. Mol. Sci. 2021, 22(19), 10589; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910589 - 30 Sep 2021

Cited by 1 | Viewed by 1998

Abstract

In birds, the zona pellucida (ZP) matrix that surrounds the ovulated oocyte—called the inner perivitelline layer—is involved in sperm–zona interaction and successful fertilization. To identify the important genes and proteins connected with the final step of egg development, next-generation sequencing and two-dimensional electrophoresis, [...] Read more.

In birds, the zona pellucida (ZP) matrix that surrounds the ovulated oocyte—called the inner perivitelline layer—is involved in sperm–zona interaction and successful fertilization. To identify the important genes and proteins connected with the final step of egg development, next-generation sequencing and two-dimensional electrophoresis, combined with mass spectrometry, were used for the analysis of mature oocytes at the F1 developmental stage. A total of 8161 genes and 228 proteins were annotated. Six subfamilies of genes, with codes ZP, ZP1–4, ZPD, and ZPAX, were identified, with the dominant expression of ZPD. The main expression site for ZP1 was the liver; however, granulosa cells may also participate in local ZP1 secretion. A ubiquitination system was identified in mature oocytes, where ZP1 was found to be the main ubiquitinated protein. Analysis of transcripts classified in estrogen receptor (ESR) signaling indicated the presence of ESR1 and ESR2, as well as a set of estrogen-dependent genes involved in both genomic and nongenomic mechanisms for the regulation of gene expression by estrogen. Oxidative phosphorylation was found to be a possible source of adenosine triphosphate, and the nuclear factor erythroid 2-related factor 2 signaling pathway could be involved in the response against oxidative stress. Oocyte–granulosa cell communication by tight, adherens, and gap junctions seems to be essential for the final step of oocyte maturation. Full article

(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)

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19 pages, 2516 KiB

Open AccessArticle

Functional Activity of Recombinant Forms of Amh and Synergistic Action with Fsh in European Sea Bass Ovary

by Cinta Zapater, Ana Rocha, Gregorio Molés, Alessia Mascoli, Soledad Ibañez, Silvia Zanuy and Ana Gómez

Int. J. Mol. Sci. 2021, 22(18), 10092; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810092 - 18 Sep 2021

Cited by 1 | Viewed by 2385

Abstract

Although anti-Müllerian hormone (AMH) has classically been correlated with the regression of Müllerian ducts in male mammals, involvement of this growth factor in other reproductive processes only recently come to light. Teleost is the only gnathostomes that lack Müllerian ducts despite having amh [...] Read more.

Although anti-Müllerian hormone (AMH) has classically been correlated with the regression of Müllerian ducts in male mammals, involvement of this growth factor in other reproductive processes only recently come to light. Teleost is the only gnathostomes that lack Müllerian ducts despite having amh orthologous genes. In adult teleost gonads, Amh exerts a role in the early stages of germ cell development in both males and females. Mechanisms involving the interaction of Amh with gonadotropin- and growth factor-induced functions have been proposed, but our overall knowledge regarding Amh function in fish gonads remains modest. In this study, we report on Amh actions in the European sea bass ovary. Amh and type 2 Amh receptor (Amhr2) are present in granulosa and theca cells of both early and late-vitellogenic follicles and cannot be detected in previtellogenic ovaries. Using the Pichia pastoris system a recombinant sea bass Amh has been produced that is endogenously processed to generate a 12–15 kDa bioactive mature protein. Contrary to previous evidence in lower vertebrates, in explants of previtellogenic sea bass ovaries, mature Amh has a synergistic effect on steroidogenesis induced by the follicle-stimulating hormone (Fsh), increasing E2 and cyp19a1a levels. Full article

(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)

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28 pages, 4531 KiB

Open AccessArticle

Differential Regulation of Gonadotropins as Revealed by Transcriptomes of Distinct LH and FSH Cells of Fish Pituitary

by Lian Hollander-Cohen, Matan Golan and Berta Levavi-Sivan

Int. J. Mol. Sci. 2021, 22(12), 6478; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126478 - 17 Jun 2021

Cited by 17 | Viewed by 5228

Abstract

From mammals to fish, reproduction is driven by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) temporally secreted from the pituitary gland. Teleost fish are an excellent model for addressing the unique regulation and function of each gonadotropin cell since, unlike mammals, they synthesize [...] Read more.

From mammals to fish, reproduction is driven by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) temporally secreted from the pituitary gland. Teleost fish are an excellent model for addressing the unique regulation and function of each gonadotropin cell since, unlike mammals, they synthesize and secrete LH and FSH from distinct cells. Only very distant vertebrate classes (such as fish and birds) demonstrate the mono-hormonal strategy, suggesting a potential convergent evolution. Cell-specific transcriptome analysis of double-labeled transgenic tilapia expressing GFP and RFP in LH or FSH cells, respectively, yielded genes specifically enriched in each cell type, revealing differences in hormone regulation, receptor expression, cell signaling, and electrical properties. Each cell type expresses a unique GPCR signature that reveals the direct regulation of metabolic and homeostatic hormones. Comparing these novel transcriptomes to that of rat gonadotrophs revealed conserved genes that might specifically contribute to each gonadotropin activity in mammals, suggesting conserved mechanisms controlling the differential regulation of gonadotropins in vertebrates. Full article

(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)

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16 pages, 1905 KiB

Open AccessArticle

Estradiol Regulates mRNA Levels of Estrogen Receptor Beta 4 and Beta 5 Isoforms and Modulates Human Granulosa Cell Apoptosis

by Alice Pierre, Anne Mayeur, Clémentine Marie, Victoria Cluzet, Jonathan Chauvin, Nelly Frydman, Michael Grynberg, Joelle Cohen-Tannoudji, Céline J. Guigon and Stéphanie Chauvin

Int. J. Mol. Sci. 2021, 22(9), 5046; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22095046 - 10 May 2021

Cited by 10 | Viewed by 2608

Abstract

Estrogen receptor beta (ERβ) plays a critical role in granulosa cell (GC) functions. The existence of four human ERβ splice isoforms in the ovary suggests their differential implication in 17β-estradiol (E2) actions on GC apoptosis causing follicular atresia. In this study, we investigated [...] Read more.

Estrogen receptor beta (ERβ) plays a critical role in granulosa cell (GC) functions. The existence of four human ERβ splice isoforms in the ovary suggests their differential implication in 17β-estradiol (E2) actions on GC apoptosis causing follicular atresia. In this study, we investigated whether E2 can regulate ERβ isoforms expression to fine tune its apoptotic activities in human GC. For this purpose, we measured by RT-qPCR the expression of ERβ isoforms in primary culture of human granulosa cells (hGCs) collected from patients undergoing in vitro fertilization, before and after E2 exposure. Besides, we assessed the potential role of ERβ isoforms on cell growth and apoptosis after their overexpression in a human GC line (HGrC1 cells). We confirmed that ERβ1, ERβ2, ERβ4, and ERβ5 isoform mRNAs were predominant over that of ERα in hGCs, and found that E2 selectively regulates mRNA levels of ERβ4 and ERβ5 isoforms in these cells. In addition, we demonstrated that overexpression of ERβ1 and ERβ4 in HGrC1 cells increased cell apoptosis by 225% while ERβ5 or ERβ2 had no effect. Altogether, our study revealed that E2 may influence GC fate by specifically regulating the relative abundance of ERβ isoforms mRNA to modulate the balance between pro-apoptotic and non-apoptotic ERβ isoforms. Full article

(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)

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Review

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20 pages, 1547 KiB

Open AccessReview

A New Perspective on Thyroid Hormones: Crosstalk with Reproductive Hormones in Females

by Bingtao Ren and Yan Zhu

Int. J. Mol. Sci. 2022, 23(5), 2708; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052708 - 28 Feb 2022

Cited by 23 | Viewed by 11714

Abstract

Accumulating evidence has shown that thyroid hormones (THs) are vital for female reproductive system homeostasis. THs regulate the reproductive functions through thyroid hormone receptors (THRs)-mediated genomic- and integrin-receptor-associated nongenomic mechanisms, depending on TH ligand status and DNA level, as well as transcription and [...] Read more.

Accumulating evidence has shown that thyroid hormones (THs) are vital for female reproductive system homeostasis. THs regulate the reproductive functions through thyroid hormone receptors (THRs)-mediated genomic- and integrin-receptor-associated nongenomic mechanisms, depending on TH ligand status and DNA level, as well as transcription and extra-nuclear signaling transduction activities. These processes involve the binding of THs to intracellular THRs and steroid hormone receptors or membrane receptors and the recruitment of hormone-response elements. In addition, THs and other reproductive hormones can activate common signaling pathways due to their structural similarity and shared DNA consensus sequences among thyroid, peptide, and protein hormones and their receptors, thus constituting a complex and reciprocal interaction network. Moreover, THs not only indirectly affect the synthesis, secretion, and action of reproductive hormones, but are also regulated by these hormones at the same time. This crosstalk may be one of the pivotal factors regulating female reproductive behavior and hormone-related diseases, including tumors. Elucidating the interaction mechanism among the aforementioned hormones will contribute to apprehending the etiology of female reproductive diseases, shedding new light on the treatment of gynecological disorders. Full article

(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)

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