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Special Issue "Hormones and Receptors in Sexual Reproduction"

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

Deadline for manuscript submissions: 28 February 2022.

Special Issue Editor

Prof. Dr. Berta Levavi-Sivan
E-Mail Website
Guest Editor
Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food, and Environment, Hebrew University of Jerusalem, Rehovot, Israel
Interests: reproduction; endocrinology; gonadotropin-hormones; growth; metabolism; fish; GPCR; hypothalamus–pituitary–gonad axis; molecular modeling; molecular docking

Special Issue Information

Dear Colleagues,

Reproduction is one of the most important concepts in biology, providing the continued existence of all species. Reproduction is controlled by the the hypothalamic–pituitary–gonadal (HPG) axis of intercommunicating neural and endocrine systems that function together in the regulation of fertility.

All reproductive processes involve hormones secreted from the anterior pituitary gland, such as the follicle-stimulating hormone (FSH) and luteinizing hormone (LH), prolactin, growth hormone (GH), adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH). Major hormones of reproduction, such as LH and FSH, directly control many aspects of gonadal development and function across vertebrates. The gene expression and secretion of pituitary gonadotropins are regulated by a plethora of neuroendocrine factors from the hypothalamus, endocrine hormones from the peripheral organs such as the gonads, and paracrine factors within the pituitary itself. The neuroenocrine control of reproduction is complex and includes Gnrhs, many neuropeptides (agouti-related peptides, cholecytokinin, galanin, isotocin, kisspeptin, neurokinin B, secretoneurine ghrelin, gonadotropin release inhibiting hormone (GnIH), spexin, neuropeptide Y), aminergic (dopamine, neurorpinephrine, serotonin) and amino acid neurotransmitters (γ-aminobutyric acid, glutamate, taurine). All these hormones act via binding to specific receptors that activate a specific signal transduction mechanism which ultimately leads to cell-type-specific responses. Receptor proteins can be classified by their location. Transmembrane receptors include ion-channel-linked receptors and G-protein-coupled receptors. Intracellular receptors are steroid receptors, which include cytoplasmic receptors and nuclear receptors.

Molecular interactions function as the core regulators of the sexual maturation and reproduction. With the development of newer techniques to study, visualize and manipulate the involved hormones and receptors, newer prespectives and possibilities have emerged for us to study. This Special Issue of International Journal of Molecular Sciences, “Hormones and Receptors in Sexual Reproduction”, aims to shed light on recent deveplopments and prespectives of these molecular mechanisms in sexual reproduction, and welcomes submissions of reviews, opinions, research studies and articles concerning relevant topics.

Prof. Berta Levavi-Sivan
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • gonadotropins
  • neuropeptides
  • kisspeptin
  • luteinizing hormone
  • follicle-stimulating hormone
  • Neurokinin B
  • spexin
  • gonadotropin-inhibitory hormone
  • somatostatin
  • reproductive endocrinology
  • sexual maturation
  • gonadal development
  • sexual behaviour
  • reproductive hormones
  • hormone–receptor complexes
  • GPCR
  • steroid hormones
  • molecular modeling
  • docking

Published Papers (3 papers)

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Research

Article
Functional Activity of Recombinant Forms of Amh and Synergistic Action with Fsh in European Sea Bass Ovary
Int. J. Mol. Sci. 2021, 22(18), 10092; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810092 (registering DOI) - 18 Sep 2021
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)
Article
Differential Regulation of Gonadotropins as Revealed by Transcriptomes of Distinct LH and FSH Cells of Fish Pituitary
Int. J. Mol. Sci. 2021, 22(12), 6478; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126478 - 17 Jun 2021
Viewed by 513
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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Article
Estradiol Regulates mRNA Levels of Estrogen Receptor Beta 4 and Beta 5 Isoforms and Modulates Human Granulosa Cell Apoptosis
Int. J. Mol. Sci. 2021, 22(9), 5046; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22095046 - 10 May 2021
Viewed by 603
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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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Differential regulation of gonadotropins as revealed by transcriptomes of distinct LH and FSH cells of fish pituitary
Authors: Berta Levavi-Sivan
Affiliation: HUJI, Israel

Title: Functional activity of recombinant forms of Amh and synergistic action with Fsh in European sea bass ovary
Authors: Cinta Zapater; Ana Rocha,; Gregorio Molés; Alessia Mascoli; Soledad Ibañez; Silvia Zanuy; Ana Gómez
Affiliation: CSIC, Spain
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 are 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 we have produced a recombinant sea bass Amh that is endogenously processed to generate a 12-15 kDa bioactive mature protein. Contrary to previous evidence in lower vertebrates, we show that, 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.

Title: Characteristics of Neurokinin-3 Receptor and its Binding Sites by Mutational Analysis
Authors: Ishwar Atre; Naama Mizrahi; Berta Levavi-Sivan
Affiliation: Hebrew University of Jerusalem
Abstract: Neurokinin B (NKB) has already been established as a key regulator in reproductive processes in fish, but little is known about the structure and functionality of NKB receptors. In the current study, we created in-silico models for the tilapia NKB receptor (tiTac3Ra), identified its putative orthosteric and allosteric binding sites and key residues involved in binding of tilapia NKB, and its functional homologue NKF. Interestingly, we observed no direct peptide interaction with their tilapia homologs F2516.44 and M2897.43 despite studies in humans suggesting their crucial role in NKB binding. Although, Ala mutations on residues F2516.44 and M2897.43 did not influence binding affinity, they significantly affect the stability of tiTac3Ra, and showed significant reduction in the receptor's activity for NKB and NKF. Further in-vitro studies indicated them to be critical to tiNKB/tiNKF-induced receptor activity. We also report the binding of NKB antagonists to tiTac3Ra, and their in-vitro and in-vivo activity on FSH and LH release and sperm production in mature tilapia males. Non-peptide NKB antagonist SB222200, had a strong inhibitory effect on Tac3Ra activation. SB222200 also decreased LH plasma levels, two hours post IP injection, changed sperm volume and the ratios of the different stages along the spermatogenesis in tilapia testes.

Title: transcriptome and proteome of turkeys hen mature oocyte at F1 developmental stage
Authors: Mariola Słowińska
Affiliation: Instytut Rozrodu Zwierząt i Badań Żywności | Institute of Animal Reproduction and Food Research
Abstract: In birds, the oocyte is highly specialized cell equipped for generating and development of the embryo. The zona pellucida (ZP) matrix that surrounds ovulated oocyte, called inner perivitelline layer (IPVL), is involved in sperm-zona interaction and successful fertilization. To identify the key genes and proteins as well as pathways associated with final step of egg coat development, a next-generation sequencing and two dimensional electrophoresis combined with mass spectrometry were used for analysis of mature oocyte at F1 developmental stage. A total of 7,666 genes and 228 proteins were annotated. The functional profiling was performed using Ingenuity Pathway Analysis (IPA). A strong overlap between IPA canonical pathways imputed from transcriptomic and proteomic data was observed. Six subfamilies of ZP genes, ZP1-4, ZPD and ZPAX were identified. IPA analysis revealed that many of the identified genes/proteins were involved in key steps of protein synthesis via eIF2, elF4 and p70S6K signaling pathways and degradation via ubiquitination. Detailed analysis of transcripts classified in estrogen receptor (ESR) signalling indicated presence of ESR1 and ESR2 and a set of estrogen-dependent genes involved in both genomic and non-genomic mechanism of regulation of gene expression by estrogen. Oxidative phosphorylation was found to be a possible source of ATP in the mature bird oocyte and nuclear factor erythroid 2–related factor signaling pathway could be involved in response against oxidative stress. The oocyte-granulosa cell communication by tight, adherens, and gap junctions seems to be essential for the final step of oocyte maturation. Here, we identified the key physiological process involved in the final stage of oocyte maturation and taking part in IPVL preparation for fertilization. The identified genes/proteins can be potentially used to characterize the specific mechanism of bird reproduction.

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