Elsevier

Life Sciences

Volume 81, Issues 25–26, 14 December 2007, Pages 1627-1637
Life Sciences

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Local serotonergic signaling in mammalian follicles, oocytes and early embryos

https://doi.org/10.1016/j.lfs.2007.09.034Get rights and content

Abstract

The involvement of neurotransmitters in mammalian female reproductive tissues has been the object of several studies in past decades. This review focuses on new evidence that serotonin (or 5-hydroxytryptamine, 5-HT) may be an important key player, acting locally in mammalian ovaries and female genital tracts where it may influence granulosa and cumulus cells as well as oocytes and early embryos. Pioneering studies reporting 5-HT in ovaries and other female reproductive tissues and cells are now complemented by the identification of specific 5-HT receptor subtypes (5-HT1D, 5-HT2A-B and 5-HT7) in granulosa or cumulus cells, oocytes and early embryos. Additional serotonergic players, including the 5-HT transporter (SERT or Slc6A4) expressed in oocytes and embryos, and the 5-HT-producing enzyme tryptophan hydroxylase-1 (TPH1) expressed in cumulus cells, now make up a complete and autonomous local serotonergic network. Direct demonstrations of intracellular Ca2+ and cAMP signaling by 5-HT in cumulus cells and its capacity to regulate progesterone secretion by granulosa cells further illustrate some of its potential functions in ovarian physiology. Recent evidence shows that mouse mothers with knocked-out TPH1 have embryos with impaired early development, establishing that maternal 5-HT is required for normal embryonic development. This local regulation of reproductive processes by 5-HT in mammals might have derived from better-known, and possibly ancestral, serotonergic networks similarly at play in several primitive animals, and potential implications for human reproduction may also be foreseen. Specific roles played by 5-HT in mammalian reproduction remain to be further investigated, and now span from steroidogenesis and oocyte maturation to early embryonic development.

Introduction

Soon after the discovery of serotonin (5-HT) by Page and co-workers (Rapport et al., 1948), it was rapidly recognized that this neurotransmitter had multiple actions in diverse body parts, mostly in blood vessels, intestinal tracts and the central nervous system (CNS). Early studies on 5-HT in female mammalian reproductive tissues date back to the 1970s, well before cloning and sequencing of the first 5-HT receptor in the late 1980s (Kobilka et al., 1987, Fargin et al., 1988). Likewise, some observed effects of 5-HT were ascribed in the past to a limited number of then known 5-HT receptors, with available pharmacological tools. Some interpretations need to be refreshed based on expansion of the family of known mammalian 5-HT receptors now numbering 14 different subtypes belonging to one of seven classes, 5-HT1 to 5-HT7. Exhaustive molecular characterizations of mammalian 5-HT receptors combined with the advent of methodological improvements in expression analyses, including RT-PCR (reverse transcription-polymerase chain reaction), EST (expressed sequence tags) detection and microarray analyses, have recently provided new opportunities to revisit the possible existence of a serotonergic network in female mammalian reproductive tissues. Recent surprising findings rejuvenate ancient presumptions that had been neglected for years, and a new perspective is now possible for reconciling scattered, if not contradictory, past reports on local serotonergic networks in female mammalian reproductive tissues.

Diverse neurotransmitters are known to be present in male and female mammalian reproductive tissues and are proposed to be involved in diverse functions. This review is restricted to 5-HT in female reproduction, and we refer the reader to reviews on other neurotransmitters in female reproductive tissues, such as acetylcholine (Mayerhofer et al., 2003, Mayerhofer and Kunz, 2005), or on better-known roles and functions of 5-HT in male reproductive tissues (Dufau et al., 1993). Although beyond the scope of our review, it has to be kept in mind that any of these communication networks may well be interacting with the serotonergic network discussed here, through intricate and possibly complex links. This review will focus on pre-implantation oocyte maturation and embryonic development when the possible source of 5-HT is exclusively maternal and not attributable to the foetus itself. We will not discuss the role of 5-HT in vascular and muscular tone of associated tissues, such as the uterus, oviduct, or placenta. 5-HT and several serotonergic effectors appear at a time corresponding approximately to days 9–11 of mouse embryonic development and their roles, especially in craniofacial and cardiac development in this period and beyond, have been reviewed by others (Lauder et al., 1988, Lauder et al., 2000, Yavarone et al., 1993, Choi et al., 1998, Buznikov et al., 2001).

Recently, renewed interest in the possible roles of serotonin in non-neural organs was fostered by discoveries illustrating unsuspected functions of the neurohormone in peripheral tissues. Indeed, while 5-HT was well-known to regulate vascular tone, cardiac and intestinal functions as well as cell proliferation in various cell types, such as fibroblasts (Van Obberghen-Schilling et al., 1991) or lymphocytes (Abdouh et al., 2001, Abdouh et al., 2004), it was also recently shown to regulate additional unrelated processes, such as osteoblast differentiation (Gustafsson et al., 2006), liver regeneration (Lesurtel et al., 2006) and mammary gland development (Matsuda et al., 2004), and to use new signaling pathways, such as serotonylation driven by intracellular 5-HT (Walther et al., 2003b). In light of this expanding list of multiple effects of 5-HT, our review proposes to examine the possibility of serotonergic regulation of reproductive processes in mammals, an unexpected function that might, in addition, have been conserved from ancestral animal groups for analogous purposes.

Section snippets

5-HT in female reproductive tissues

In early reports, 5-HT was detected in the oviducts, uterus and ovaries of various rodent species, including rats, hamsters and mice (see Table 1). The origin of neurotransmitters detected in ovaries, including 5-HT, was often tentatively ascribed to nerve terminals extending within the ovary or to neighbouring storage sites, such as platelets, or infiltrating mast cells (Amenta et al., 1992). 5-HT itself was reported in rat ovaries as well as oviducts and uterus as measured by chemical

Identification of 5-HT receptors in ovarian tissues and cells

Mammalian 5-HT receptors are divided into seven distinct classes (5-HT1 to 5-HT7) comprising 14 subtypes sharing similarities in their amino acid sequence, pharmacological properties and signaling mechanisms. All are G protein-coupled receptors exhibiting typical rhodopsin-like seven transmembrane domains except for one class, 5-HT3, which is a ligand-gated cation channel. Activated receptors belonging to the 5-HT1 class promote a decrease in cellular cAMP, those belonging to the 5-HT4, 5-HT6

Other serotonergic effectors detected in ovarian tissues and cells

Besides 5-HT, as ligand, and various specific receptors, a complete local serotonergic network requires additional components to be functional, including an efficient source or local production of 5-HT itself, a transport mechanism to remove extracellular 5-HT and an intracellular recycling or degrading mechanism. One major challenge in early research on the local effects of serotonin was elucidation of neurohormone source apart from regular innervation of tissues. Local 5-HT production by gut

Serotonergic effector knockout models

Several knockout mouse models for various serotonergic effectors have been produced, including numerous 5-HT receptors as well as TPH1 and SERT. Among the knocked-out 5-HT receptors, those detected in reproductive cells or tissues are 5-HT7, 5-HT1D and 5-HT2A and 5-HT2B receptors. The extent of anomalies reported for the absence of one or the other of these receptors varies widely and ranges from mildly altered thermal regulation (5-HT7) (Hedlund et al., 2003), to severe and lethal cardiac

Potential roles for a local serotonergic network in ovarian physiology and early embryonic development

While previous sections have presented evidence that mammalian ovaries, oocytes and embryos do indeed experience an environment with all components required for functional serotonergic regulation, distinctly-identified physiological roles for 5-HT are only starting to be uncovered (see Table 2). As seen above, knockout models suggest that deletions of most serotonergic effectors identified in mouse ovaries do not result in infertility or early embryonic anomalies and, thus, are dispensable or

Widespread serotonergic regulation of female reproduction in the animal kingdom

While the involvement of 5-HT in female reproduction is only beginning to be uncovered in mammals, 5-HT has already emerged as a key regulator of reproduction in several other distant animal groups. It was first discovered that 5-HT was able to induce spawning in numerous species of marine bivalve molluscs, such as clams and oysters, when injected directly into the gonads of ripe animals (Matsutani and Nomura, 1982, Gibbons and Castagna, 1984, Hirai et al., 1988, Ram et al., 1993, Fong et al.,

Human health issues

Despite limited teratogenic effects of SSRIs in animal gestations subjected to higher doses than the maximal recommended dosage in humans (Hallberg and Sjoblom, 2005), several studies paid attention to possible adverse pregnancy outcomes due to SSRI use in women with depression or other mood disorders. This is due to expanding prescriptions of SSRIs that result, among the 4 million live births in the United States each year, in an estimated 90,000 infants (2.3%) being prenatally exposed to

Conclusion

This review summarizes numerous observations that 5-HT is likely involved locally in diverse reproductive processes in mammals. Recent advances have more precisely identified some key components, establishing the existence of a complete and autonomous serotonergic network in female reproductive tissues. Specific developmental defects may be attributed to dysregulation of serotonergic signaling in reproductive tissues and cells. Analogous, though not identical, serotonergic regulation of

Acknowledgements

We thank Ovid Da Silva, editor, Research centre, Centre hospitalier de l'Université de Montréal, for editorial revision of the manuscript. F.D. is supported by a discovery grant from the Natural Sciences and Engineering Council of Canada (NSERC-Canada). P.A. was a recipient of graduate fellowships from the Fonds pour la formation de chercheurs et l'aide à la recherche (FCAR-Québec) and the Université de Montréal.

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