Female Sexual Development Research Articles

Hypothalamic Tumor Necrosis Factor-α Converting Enzyme Mediates Excitatory Amino Acid-Dependent Neuron-to-Glia Signaling in the Neuroendocrine Brain

Glial erbB1 receptors play a significant role in the hypothalamic control of female puberty. Activation of these receptors by transforming growth factor alpha (TGFalpha) results in production of prostaglandin E2, which then stimulates luteinizing hormone releasing hormone (LHRH) neurons to secrete LHRH, the neuropeptide controlling sexual development. Glutamatergic neurons set in motion this glia-to-neuron signaling pathway by transactivating erbB1 receptors via coactivation of AMPA receptors (AMPARs) and metabotropic glutamate receptors (mGluRs). Because the metalloproteinase tumor necrosis factor alpha converting enzyme (TACE) releases TGFalpha from its transmembrane precursor before TGFalpha can bind to erbB1 receptors, we sought to determine whether TACE is required for excitatory amino acids to activate the TGFalpha-erbB1 signaling module in hypothalamic astrocytes, and thus facilitate the advent of puberty. Coactivation of astrocytic AMPARs and mGluRs caused extracellular Ca2+ influx, a Ca2+/protein kinase C-dependent increase in TACE-like activity, and enhanced release of TGFalpha. Within the hypothalamus, TACE is most abundantly expressed in astrocytes of the median eminence (ME), and its enzymatic activity increases selectively in this region at the time of the first preovulatory surge of gonadotropins. ME explants respond to stimulation of AMPARs and mGluRs with LHRH release, and this response is prevented by blocking TACE activity. In vivo inhibition of TACE activity targeted to the ME delayed the age at first ovulation, indicating that ME-specific changes in TACE activity are required for the normal timing of puberty. These results suggest that TACE is a component of the neuron-to-glia signaling process used by glutamatergic neurons to control female sexual development.

Integrating hormones and other biological factors into a developmental systems model of adolescent female sexuality

This chapter discusses biological contributions to adolescent female sexual development and, based on a developmental systems framework, suggests future research directions.

Expression of Three Gene Families Encoding Cell–Cell Communication Molecules in the Prepubertal Nonhuman Primate Hypothalamus

Transsynaptic and glial-neuronal communication are important components of the mechanism underlying the pubertal activation of luteinizing hormone-releasing hormone (LHRH) secretion. The molecules required for the architectural organization of these cell-cell interactions have not been identified. We now show that the hypothalamus of the prepubertal female rhesus monkey expresses a multiplicity of genes encoding three families of adhesion/signalling proteins involved in the structural definition of both neurone-to-neurone and bi-directional neurone-glia communication. These include the neurexin/neuroligin (NRX/NRL) and protocadherin-alpha (PCDHalpha) families of synaptic specifiers/adhesion molecules, and key components of the contactin-dependent neuronal-glial adhesiveness complex, including contactin/F3 itself, the contactin-associated protein-1 (CASPR1), and the glial receptor protein tyrosine phosphatase beta. Prominently expressed among members of the NRX family is the neurexin isoform involved in the specification of glutamatergic synapses. Although NRXs, PCDHalphas and CASPR1 transcripts are mostly detected in neurones, the topography of expression appears different. NRX1 mRNA-containing neurones are scattered throughout the hypothalamus, PCDHalpha mRNA transcripts appear more abundant in neurones of the arcuate nucleus and periventricular region, and neurones positive for CASPR1 mRNA exhibit a particularly striking distribution pattern that delineates the hypothalamus. Examination of LHRH neurones, using the LHRH-secreting cell line GT1-7, showed that these cells contain transcripts encoding NRXs and one of their ligands (NRL1), at least one PCDHalpha (CNR-8/PCDHalpha10), and the CASPR1/contactin complex. The results indicate that the prepubertal female monkey hypothalamus contains a plethora of adhesion/signalling molecules with different but complementary functions, and that an LHRH neuronal cell line expresses key components of this structural complex. The presence of such cell-cell communication machinery in the neuroendocrine brain suggests an integrated participation of their individual components in the central control of female sexual development.

ErbB-1 and erbB-4 Receptors Act in Concert to Facilitate Female Sexual Development and Mature Reproductive Function

Glial erbB-1 and erbB-4 receptors are key components of the process by which neuroendocrine glial cells control LHRH secretion and the onset of female puberty. We now provide evidence that these two signaling systems work in a coordinated fashion to control reproductive function. To generate animals carrying functionally impaired erbB-1 and erbB-4 receptors, we crossed Waved 2 (Wa-2+/+) mice harboring a point mutation of the erbB-1 receptor with mice expressing a dominant-negative erbB-4 receptor in astrocytes. In comparison to single-deficient mice, double-mutant animals exhibited a further delay in the onset of puberty and a strikingly diminished adult reproductive capacity. Ligand-dependent erbB receptor phosphorylation and erbB-mediated MAPK (ERK 1/2) phosphorylation were impaired in mutant astrocytes. Wa-2+/+ or double-mutant astrocytes failed to respond to TGF alpha with production of prostaglandin E2, one of the factors mediating the stimulatory effect of astroglial erbB receptor activation on LHRH release. Medium conditioned by Wa-2+/+ or double-mutant astrocytes treated with TGF alpha failed to stimulate LHRH release from GT1-7 cells. The LH response to ovariectomy was significantly attenuated in mutant mice in comparison with wild-type controls. Although the Wa-2 mutation affects all cells bearing erbB-1 receptors, these results suggest that a major defect underlying the reproductive defects of animals with impaired erbB signaling is a decreased ability of glial cells to stimulate LHRH release. Thus, a coordinated involvement of erbB-1 and erbB-4 signaling systems is required for the normalcy of sexual development and the maintenance of mature female reproductive function.

Wnt4 is required for proper male as well as female sexual development

Genes previously implicated in mammalian sexual development have either a male- or female-specific role. The signaling molecule WNT4 has been shown to be important in female sexual development. Lack of Wnt4 gives rise to masculinization of the XX gonad and we showed previously that the role of WNT4 was to inhibit endothelial and steroidogenic cell migration into the developing ovary. Here we show that Wnt4 also has a function in the male gonad. We find that Sertoli cell differentiation is compromised in Wnt4 mutant testes and that this defect occurs downstream of the testis-determining gene Sry but upstream of Sox9 and Dhh, two early Sertoli cell markers. Genetic analysis shows that this phenotype is primarily due to the action of WNT4 within the early genital ridge. Analysis of different markers identifies the most striking difference in the genital ridge at early stages of its development between wild-type and Wnt4 mutant embryos to be a significant increase of steroidogenic cells in the Wnt4 −/− gonad. These results identify WNT4 as a new factor involved in the mammalian testis determination pathway and show that genes can have a specific but distinct role in both male and female gonad development.

Phthalate Exposure and Early Thelarche

Phthalate Exposure and Early Thelarche

Hormones and history: The evolution and development of primate female sexuality

Sexual behavior is required for reproduction in internally fertilizing species but poses significant social and physical risks. Females in many nonprimate species have evolved physical and behavioral mechanisms restricting sexual behavior to when females are fertile. The same hormones producing female fertility also control these mechanisms, assuring that sex only occurs when reproduction is possible. In contrast to nonprimate mammals, hormones do not regulate the capacity to engage in sex infernale anthropoid primates, uncoupling fertility and the physical capacity to mate. Instead, in primates, sexual motivation has become the primary coordinator between sexual behavior and fertility. This dependence upon psychological mechanisms to coordinate physiology with behavior is possibly unique to primates, including humans, and allows a variety of nonphysiological influences, particularly social context, to regulate sexual behavior. The independence between hormonal state and sexual behavior allows sex to be used for social purposes. This complex regulation of primate sexuality develops during adolescence, where female monkeys show both hormonally influenced sexual motivation and socially modulated sexual behavior. We present findings from rhesus monkeys illustrating how social context and hormonal state interact to modulate adolescent and adult sexuality. It is argued that this flexibility in sexual behavior, combined with a tight regulation of sexual motivational systems by reproductive hormones, allows sexual behavior to be used for nonreproductive purposes while still assuring its occurrence during periods of female fertility. The evolutionary pressures that produced such flexibility in sexual behavior remain puzzling, but may reflect the importance of sexuality to primate social attraction and cohesion.

Compromised reproductive function in adult female mice selectively expressing mutant ErbB-1 tyrosine kinase receptors in astroglia.

The ErbB-1 tyrosine kinase receptor plays critical roles in regulating physiological functions. This receptor-mediated signaling in astroglia has been implicated in controlling female sexual development via activating neurons that release LH-releasing hormone (LHRH), the neuropeptide required for the secretion of LH. It remains unknown whether astroglial ErbB-1 receptors are necessary for maintaining normal adult reproductive function. Here we provide genetic evidence that astroglia-specific and time-controlled disruption of ErbB-1 receptor signaling by expressing mutant ErbB-1 receptors leads to compromised reproduction due to alteration in LHRH neuron-controlled secretion of LH in adult female mice. Therefore, astroglial ErbB-1 receptors are required for controlling LHRH neuronal function and thus maintaining adult reproduction, suggesting that compromised astroglial ErbB-1 signaling may also contribute to reproductive abnormalities in aging females.

Normal Female Sexual Development Requires Neuregulin–erbB Receptor Signaling in Hypothalamic Astrocytes

The initiation of mammalian puberty requires the activation of hypothalamic neurons secreting the neuropeptide luteinizing hormone-releasing hormone (LHRH). It is thought that this activation is caused by changes in trans-synaptic input to LHRH neurons. More recently, it has been postulated that the pubertal increase in LHRH secretion in female animals also requires neuron-glia signaling mediated by growth factors of the epidermal growth factor (EGF) family and their astrocytic erbB receptors. Although it appears clear that functional astrocytic erbB1 receptors are necessary for the timely advent of puberty, the physiological contribution that erbB4 receptors may make to this process has not been established. To address this issue, we generated transgenic mice expressing a dominant-negative erbB4 receptor (DN-erbB4) under the control of the GFAP promoter, which targets transgene expression to astrocytes. DN-erbB4 expression is most abundant in hypothalamic astrocytes, where it blocks the ligand-dependent activation of glial erbB4 and erbB2 receptors, without affecting erbB1 (EGF) receptor signaling. Mice carrying the transgene exhibit delayed sexual maturation and a diminished reproductive capacity in early adulthood. These abnormalities are related to a deficiency in pituitary gonadotropin hormone secretion, caused by impaired release of LHRH, the hypothalamic neuropeptide that controls sexual development. In turn, the reduction in LHRH release is caused by the inability of hypothalamic astrocytes to respond to neuregulin (NRG) with production of prostaglandin E(2), which in wild-type animals mediates the stimulatory effect of astroglial erbB receptor activation on neuronal LHRH release. Thus, neuron-astroglia communication via NRG-erbB4/2 receptor signaling appears to be essential for the timely unfolding of the developmental program by which the brain controls mammalian sexual maturation.

Multiple functions of mfa-1, a putative pheromone precursor gene of Neurospora crassa.

A putative pheromone precursor gene of Neurospora crassa, mfa-1 (which encodes mating factor a-1), was identified as the most abundant clone in starved mycelial and perithecial cDNA libraries. Northern analysis demonstrated high mfa-1 expression in all mating type a tissues and suggested low expression levels in mat A tissues. The mfa-1 gene was expressed as an approximately 1.2-kb transcript predicted to encode a 24-residue peptide, followed by a long 3' untranslated region (3' UTR). The predicted MFA1 sequence showed 100% sequence identity to PPG2 of Sordaria macrospora and structural similarity (a carboxy-terminal CAAX motif) to many hydrophobic fungal pheromone precursors. Mutants with a disrupted open reading frame (ORF) in which the critical cysteine residue had been changed to a nonprenylatable residue, tyrosine (YAAX mutants), were isolated, as were mfa-1 mutants with intact ORFs but multiple mutations in the 3' noncoding region (CAAX mutants). The 3' UTR is required for the full range of mfa-1 gene activity. Both classes of mutants showed delayed and reduced vegetative growth (which was suppressed by supplementation with a minute amount [30 micro M] of ornithine, citrulline, or arginine), as well as aberrant sexual development. When crossed as female parents to wild-type males, the CAAX and YAAX mutants showed greatly reduced ascospore production. No ascospores were produced in homozygous mfa-1 crosses. As males, YAAX mat a mutants were unable to attract wild-type mat A trichogynes (female-specific hyphae) or to initiate sexual development, while CAAX mat a mutants were able to mate and produce sexual progeny despite their inability to attract mat A trichogynes. In the mat A background, both CAAX and YAAX mutants showed normal male fertility but defective vegetative growth and aberrant female sexual development. Thus, the mfa-1 gene appears to have multiple roles in N. crassa development: (i) it encodes a hydrophobic pheromone with a putative farnesylated and carboxymethylated C-terminal cysteine residue, required by mat a to attract trichogynes of mat A; (ii) it is involved in female sexual development and ascospore production in both mating types; and (iii) it functions in vegetative growth of both mating types.

Female “tweens” and sexual development

Sexual development as a component of interpersonal relationships is essential to healthy personality development. Nurses, as health professionals who advise and counsel “tweens” (early adolescent females) in a variety of settings, have important roles to play in promoting their healthy sexual development. To date, empirical documentation has contributed to health professionals' ability to describe factors that influence early sexual debuts, but it has contributed minimally to their understanding of the processes of sexual development. The purposes of this article are (a) to generate thoughtful discussions about the sexual development of early adolescent females and (b) to discuss how societal constructions of female sexual development and identity create particular challenges for open communication about sexual expression. Copyright 2002, Elsevier Science (USA). All rights reserved.

Intersex, a gene required for female sexual development in Drosophila, is expressed in both sexes and functions together with doublesex to regulate terminal differentiation.

Previous genetic studies indicated intersex (ix) functions only in females and that it acts near the end of the sex determination hierarchy to control somatic sexual differentiation in Drosophila melanogaster. We have cloned ix and characterized its function genetically, molecularly and biochemically. The ix pre-mRNA is not spliced, and ix mRNA is produced in both sexes. The ix gene encodes a 188 amino acid protein, which has a sequence similar to mammalian proteins thought to function as transcriptional activators, and a Caenorhabditis elegans protein that is thought to function as a transcription factor. Bringing together the facts that (1) the ix phenotype is female-specific and (2) functions at the end of the sex determination hierarchy, yet (3) is expressed sex non-specifically and appears likely to encode a transcription factor with no known DNA-binding domain, leads to the inference that ix may require the female-specific protein product of the doublesex (dsx) gene in order to function. Consistent with this inference, we find that for all sexually dimorphic cuticular structures examined, ix and dsx are dependent on each other to promote female differentiation. This dependent relationship also holds for the only known direct target of dsx, the Yolk protein (Yp) genes. Using yeast 2-hybrid assay, immunoprecipitation of recombinant tagged IX and DSX proteins from Drosophila S2 cell extracts, and gel shifts with the tagged IX and DSX(F) proteins, we demonstrate that IX interacts with DSX(F), but not DSX(M). Taken together, the above findings strongly suggest that IX and DSX(F) function in a complex, in which IX acts as a transcriptional co-factor for the DNA-binding DSX(F).

The Little Mermaid: Hans Christian Andersen's Feminine Identification

While verbally transmitted fairy tales express universal human concerns, the literary fairy tale, the written creation of an individual author, permits a psychodynamic understanding of the writer. The little mermaid's willingness to undergo the pain and mutilation involved in the loss of both her tail and was voice in order to become a mortal and marry a prince has been regarded as illustrating problems in female sexual development. However, a review of Hans Christian Andersen's biographical data indicates that the story also represents his unconscious homosexual conflicts and supports Freud's concept of the role of castration anxiety in the negative Oedipus complex.

TTF-1, a Homeodomain Gene Required for Diencephalic Morphogenesis, Is Postnatally Expressed in the Neuroendocrine Brain in a Developmentally Regulated and Cell-Specific Fashion

TTF-1 is a member of the Nkx family of homeodomain genes required for morphogenesis of the hypothalamus. Whether TTF-1, or other Nkx genes, contributes to regulating differentiated hypothalamic functions is not known. We now report that postnatal hypothalamic TTF-1 expression is developmentally regulated and associated with the neuroendocrine process of female sexual development. Lesions of the hypothalamus that cause sexual precocity transiently activate neuronal TTF-1 expression near the lesion site. In intact animals, hypothalamic TTF-1 mRNA content also increases transiently, preceding the initiation of puberty. Postnatal expression of the TTF-1 gene was limited to subsets of hypothalamic neurons, including LHRH neurons, which control sexual maturation, and preproenkephalinergic neurons of the lateroventromedial nucleus of the basal hypothalamus, which restrain sexual maturation and facilitate reproductive behavior. TTF-1 mRNA was also detected in astrocytes of the median eminence and ependymal/subependymal cells of the third ventricle, where it colocalized with erbB-2, a receptor involved in facilitating sexual development. TTF-1 binds to and transactivates the erbB-2 and LHRH promoters, but represses transcription of the preproenkephalin gene. The singular increase in hypothalamic TTF-1 gene expression that precedes the initiation of puberty, its highly specific pattern of cellular expression, and its transcriptional actions on genes directly involved in neuroendocrine reproductive regulation suggest that TTF-1 may represent one of the controlling factors that set in motion early events underlying the central activation of mammalian puberty.

P02.288 Biological factors in female sexual development

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Tomboy Tales: The rural, nature and the gender of childhood

By following and connecting certain well-trodden routes through constructions of childhood, it is possible to arrive at a point at which the 'natural' gender of childhood is apparently male. This is indicated by the fact that girls are often termed 'tomboys' in both popular and lay discourses, even when they are partaking in what are seen to be the purest, most ideal childhoods which are present in notions of country childhood idylls. Children, nature, and the countryside as surrogate nature, are all seen as innocent, and thus notions of idyllic 'natural' country childhoods become a powerful force. Heavily influenced by romantic constructions of, and connections between, childhood, nature and the countryside, such views, it will be shown, leave little space for girl children to adopt female identities. The author suggests that this ideal association of male children and nature, and the accompanying notion that it is the development of female sexuality which in particular marks a departure from the natural state of childhood, and thus ends childhood, merits consideration. This is particularly so in the contexts of various discourses, such as romanticism, feminism and ecofeminism, which have explored links between the female and the natural. The aim is not to challenge these constructions and theorisations of gender and nature directly, but rather to show how the introduction of the notion of childhood might cross-cut, problematise and even illuminate them to some degree.

Ovarian development and spawning in relation to the moult cycle in Northern krill, Meganyctiphanes norvegica (Crustacea: Euphausiacea), along a climatic gradient

Adaptive processes linked to reproduction were studied comparatively for three populations of Northern krill, Meganyctiphanes norvegica (M. Sars, 1857), sampled during winter and summer cruises in the Clyde Sea (W Scotland), the Kattegat (E Denmark), and the Ligurian Sea (NW Mediterranean). The aim was to investigate the functional relationship between egg production and moulting under contrasted climatic and environmental conditions. A staging system for female sexual development established for live krill was complemented by a histological study of the ovary at various developmental steps. During the reproductive season, all adult female krill were engaged in cyclical egg production. During experiments, female krill released one batch of mature oocytes in one or two spawning events. The ovary of postspawn female krill still contained developing oocytes for another egg batch. In the non-reproductive period, all female krill had a resting ovary. Ovarian structure and pattern of egg production were identical in the three populations, but seasonal timing of egg production was different. The model proposed for the Ligurian population of the annual cycle of ovarian development can be extended to the other two populations, taking into account the seasonal characteristics of each site. Random field samples were staged simultaneously for moult cycle and for sexual development. Moult stages and the seasonal variation of the intermoult period were studied for the Kattegat population using multi-year data and compared to data obtained during summer/winter cruises in the Clyde and the Ligurian Sea. At the three sites, intermoult period was shorter and temperature-dependent during the reproductive period, concurrent with the season of greatest food availability. During most of the year and the period of sexual rest, moulting activity was reduced. The relationship between spawning and the moult cycle was studied comparatively for the three populations. Eggs were released during the premoult phase of a “spawning moult cycle”, in one or two spawnings associated with apolysis and Moult Stage D1, respectively. Yolk accumulation for the next egg batch was completed during an alternating “vitellogenic moult cycle”. A model for the timing of cyclical egg production in relation to moulting, as proposed for the Kattegat, can be extended to the other populations, taking into account intermoult period variation with temperature. Temperature appeared to be the principal environmental factor controlling growth (through moulting) and egg production during the reproductive season, in connection with favourable trophic conditions.

Female development in mammals is regulated by Wnt-4 signalling.

In the mammalian embryo, both sexes are initially morphologically indistinguishable: specific hormones are required for sex-specific development. Mullerian inhibiting substance and testosterone secreted by the differentiating embryonic testes result in the loss of female (Mullerian) or promotion of male (Wolffian) reproductive duct development, respectively. The signalling molecule Wnt-4 is crucial for female sexual development. At birth, sexual development in males with a mutation in Wnt-4 appears to be normal; however, Wnt-4-mutant females are masculinized-the Mullerian duct is absent while the Wolffian duct continues to develop. Wnt-4 is initially required in both sexes for formation of the Mullerian duct, then Wnt-4 in the developing ovary appears to suppress the development of Leydig cells; consequently, Wnt-4-mutant females ectopically activate testosterone biosynthesis. Wnt-4 may also be required for maintenance of the female germ line. Thus, the establishment of sexual dimorphism is under the control of both local and systemic signals.

The Effect of the Aromatase Inhibitor Fadrozole and Two Polynuclear Aromatic Hydrocarbons on Sex Steroid Secretion by Ovarian Follicles of Coho Salmon

A variety of endogenous and exogenous factors can influence sex steroid production by salmon ovarian follicles and ultimately impact reproductive development. We examined the effect of an aromatase inhibitor, fadrozole, and common environmental contaminants (PAHs) on sex steroid secretion by ovarian follicles. Ovarian follicles of coho salmon were incubatedin vitrowith various concentrations of testosterone (0.10–0.40 μM) and fadrozole (10 and 100 μM), or with varying doses (between 0.05 and 5.0 μM) of the PAHs β-naphthoflavone (BNF) and 20-methylcholanthrene (20-MC). 17β-Estradiol secretion was significantly reduced when follicles were incubated in the presence of fadrozole, BNF, or 20-MC. In contrast, 17β-estradiol production by ovarian follicles increased in a dose-dependent manner when incubated with increasing doses of the aromatizable androgen testosterone. Although increasing doses of PAHs significantly reduced follicular 17β-estradiol production no effect on testosterone secretion was observed. Hence, both fadrozole and PAHs can significantly reduce 17β-estradiol secretion by salmon ovarian follicles and may affect female sexual development.

The role of growth factors in the neuroendocrine control of female sexual development

The onset of mammalian puberty requires a sustained increase in the episodic secretion of luteinizing hormone-releasing hormone (LHRH) from the hypothaiamus. This change is not initiated by LHRH neurons themselves but is instead brought about by the activation of “upstream” regulatory elements located in cells functionally connected to the LHRH neuronal network. Until now, this entire control system was thought to be neuronal and to function exclusively via transsynaptic communication. Recent studies, however, have suggested that LHRH neuronal function is also controlled by molecules of glial origin. Transforming growth factor-α was identified as one of these regulatory signals and was shown to be involved in the control of both normal and precocious puberty. Transforming growth factor-α may epitomize a group of related glial-derived growth factors involved in the developmental control of LHRH release.