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PubMed2001

X-Y translocations and sex differentiation.

Translocations involving the X and Y chromosomes are often associated with anomalies of gonadal development. Transfer of Yp sequences, including the testis-determining SRY gene, to the terminal portion of the short arm of the X chromosome is associated with 46,XX maleness and in rare cases 46,XX true hermaphroditism. Three classes of XX males have been defined on the basis of the extent of Y material transferred to the X chromosome. In one class, the transfer of material involves aberrant recombination between two highly homologous genes, PKRX and PKRY, and there is evidence to suggest that this interchange is influenced by the Y chromosome background. Other types of X-Y translocations associated with anomalies of sex differentiation include Xp-Yq translocations, which result in a functional disomy of Xp sequences including the DSS locus and are associated with 46,XY complete or partial gonadal dysgenesis. In rare cases Yp-Xq translocations have been described in association with 46,XX maleness.

Chromosome Mapping↗
PubMed2005

Parasitism in fish--an endocrine modulator of ecological relevance?

Wild bream (Abramis brama) were collected from the river Elbe, and the influences of parasitic infection by the tapeworm Ligula intestinalis on endocrine and related functions (vitellogenin [VTG]; plasma sex steroids: 17beta-estradiol [E2], 11-ketotestosterone [11-KT] and testosterone [T]; relative gonad [GSI] and liver [HSI] growth; maturation stages of germ cells [MS]; prominence of spawning tubercles [STI]) were investigated. Distinct regional differences in infection rates of bream with L. intestinalis were observed along the Elbe with the highest prevalences at the Czech border (up to 45%) and Magdeburg (up to 65%), areas that are heavily contaminated with complex mixtures of organic chemicals and metals. Parasitized fish of both sexes had significantly lower GSIs and poorly developed gonads (low MS). In males, a significant reduction in the prominence of spawning tubercles occurred. Infected females had significantly lower plasma VTG concentrations. A selective suppression of the sex steroids 11-KT and E2 was observed in male and female bream, respectively. Testosterone was not affected in the same manner in fish of both sexes. At sites with an elevated prevalence of L. intestinalis, the extent of the infection of an individual was significantly correlated with the suppression of the measured biomarkers. However, when applying a linear model to compare regional differences in infection prevalence with biological parameters, not all of the observed differences could be explained by parasitization by L. intestinalis. This indicates that other factors such as pollution may have contributed to the effects on reproductive and endocrine processes that occurred along the river. Given that sites with high prevalences of L. intestinalis were also characterized by elevated pollution, it is possible that there exists a combinatory effect of both pollution and parasitization that can have a serious impact on the reproductive capacity of a population, such as was observed at the sampling site at Magdeburg.

Animals↗
PubMed2005

Positional cloning of the PIS mutation in goats and its impact on understanding mammalian sex-differentiation.

In goats, the PIS (polled intersex syndrome) mutation is responsible for both the absence of horns in males and females and sex-reversal affecting exclusively XX individuals. The mode of inheritance is dominant for the polled trait and recessive for sex-reversal. In XX PIS-/- mutants, the expression of testis-specific genes is observed very precociously during gonad development. Nevertheless, a delay of 4-5 days is observed in comparison with normal testis differentiation in XY males. By positional cloning, we demonstrate that the PIS mutation is an 11.7-kb regulatory-deletion affecting the expression of two genes, PISRT1 and FOXL2 which could act synergistically to promote ovarian differentiation. The transcriptional extinction of these two genes leads, very early, to testis-formation in XX homozygous PIS-/- mutants. According to their expression profiles and bibliographic data, we propose that FOXL2 may be an ovary-differentiating gene, and the non-coding RNA PISRT1, an anti-testis factor repressing SOX9, a key regulator of testis differentiation. Under this hypothesis, SRY, the testis-determining factor would inhibit these two genes in the gonads of XY males, to ensure testis differentiation.

Animals↗
PubMed1995

Sexual differentiation of reproductive tissue in bivalve molluscs: identification of male associated polypeptide in the mantle of Mytilus galloprovincialis Lmk.

We have addressed the question of sexual reproductive tissue dimorphism in bivalve molluscs, Mytilus galloprovincialis Lmk, which is a stable gonochoric species although with no apparent differences in gonad morphology of both sexes. At all periods of the annual cycle the proteins specific of male/female gonads were identified. One of these proteins, "male-associated polypeptide" with apparent MW 39 kDa (MAP-39), has been biochemically and immunochemically characterized. MAP-39 concentration in male mature gonads achieved up to 10% of the total soluble protein while in female ones only traces of this protein could be detected. In male mantle, MAP-39 expression was associated with the process of gonad development and maturation as well as gamete spawning, although this polypeptide has been localized in fibroblast-like cells, membrane of follicles and connective tissue matrix of the mantle but not in germinal cells.

Animals↗
PubMed2005

Analysis of hypomorphic KitlSl mutants suggests different requirements for KITL in proliferation and migration of mouse primordial germ cells.

Germ cell development in mice is initiated when a small number of primordial germ cells (PGCs) are set aside from somatic cells during gastrulation. In the subsequent 4 to 5 days, PGCs enter the hindgut, undergo a directed migration away from the hindgut into the developing gonads, and undergo a massive increase in cell number. It is well established that Kit ligand (KITL, also known as stem cell factor and mast cell growth factor) is required for the survival and proliferation of PGCs. However, there is little information on a direct role for KITL in PGC migration. By comparing the effects of multiple Kitl mutations, including two N-ethyl-N-nitrosourea-induced hypomorphic mutations, we were able to distinguish stages of PGC development that are preferentially affected by certain mutations. We provide evidence that the requirements for KITL in proliferation are different in PGCs before and after they start migrating, and different levels of KITL function are required to support PGC proliferation and migration. This study illustrates the usefulness of an allelic series of mutations to dissect developmental processes and suggests that these mutants may be useful for further studies of molecular mechanisms of KITL functions in gametogenesis.

Animals↗
PubMed1982

Changes in serum FSH concentrations in the pig during development.

Serum FSH concentrations were measured in fetal and prepubertal pigs between 40 days postcoitum and 25 weeks after birth. In addition, serum FSH was estimated in prepubertal, unilaterally cryptorchid, freemartin and castrated pigs. The average serum FSH concentrations in male and female fetuses was low (less than 2 ng/ml) until 80 days p.c. During the remaining fetal period, concentrations in females were elevated (7.9 +/- 0.4 ng/ml) and remained fairly constant after birth (16.3 +/- 0.8 ng/ml). In the male, serum FSH concentrations gradually rose to 22.5 +/- 5.5 ng/ml during the first 3 weeks after birth and declined thereafter. The changes in FSH concentrations in male pigs are reflected in gonadal-development. In contrast, in fetal and prepubertal females, ovarian development seems not to be influenced by changes in serum FSH concentrations. Unilateral cryptorchidism did not affect serum FSH concentrations. After castration, however, concentrations rose significantly. In freemartin pigs concentrations were similar to those in female pigs.

Animals↗
PubMedDate not supplied

Juvenile hormone mediates a trade-off between primary and secondary sexual traits in stalk-eyed flies.

Trade-offs between developing body parts may contribute to variation in allometric scaling relationships in a variety of taxa. Experimental evidence indicates that both circulating levels of juvenile hormone (JH) and sensitivities of developing body parts to JH can influence morphology in polyphenic insects. However, the extent to which JH may regulate both the development of traits that scale continuously with body size and trade-offs between these traits is largely unknown. Here, I present evidence that the JH analog methoprene applied to final instar larvae of a stalk-eyed fly (Cyrtodiopsis dalmanni) can induce males to produce larger eye-stalks relative to their body size. Examination of testis growth, sperm transfer, and egg maturation indicates that JH induces a trade-off between eye-span and gonad development in adult males, but not females. Age at sexual maturity was unaffected by larval JH applications to either sex. Collectively, these results are consistent with JH-mediated allocation of resources to eye-span at the expense of testes, and indicate potential costs for the production of an exaggerated trait.

Age Factors↗
PubMed2001

Hypomorphic phenotype in mice with pituitary-specific knockout of steroidogenic factor 1.

The bacteriophage Cre recombinase provides a powerful approach for tissue-specific gene inactivation. Using a Cre transgene driven by the common alpha subunit of glycoprotein hormones (alphaGSU-Cre), we have previously inactivated steroidogenic factor 1 (SF-1) in the anterior pituitary, causing hypogonadotropic hypogonadism with sexual infantilism, sterility, and severe gonadal hypoplasia. We now explore the molecular mechanisms underlying a hypomorphic gonadal phenotype in mice carrying two floxed SF-1 alleles (F/F) relative to mice carrying one recombined and one floxed allele (F/R). Because their Cre-mediated disruption of the locus encoding SF-1 was less efficient, alphaGSU-Cre, F/F mice retained some gonadotropin-expressing cells in the anterior pituitary, thereby stimulating some gonadal function. This novel in vivo model for exploring the effects of differing levels of gonadotropins on gonadal development highlights the need for careful genotype-phenotype comparisons in studies using Cre recombinase to produce tissue-specific knockouts.

Animals↗
PubMed2003

Testicular dysgenesis syndrome.

In the Western world fertility rates are low and infertility is a major health problem. Unofficial statistics from Denmark reveal that about 6% of all Danish children are now born after assisted reproduction techniques, including in vitro fertilization, intracytoplasmic sperm injection, donor insemination or homologous insemination. However, there are no retrospective data on trends in fecundity (ability to conceive). We, and others, have focused on some aspects of adverse trends in male reproductive health such as the rising incidence of testicular cancer, low and probably declining semen quality, high and possibly increasing frequencies of undescended testes and hypospadias. Due to medical specialization and the different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, for instance paediatric endocrinologists, urologists, andrologists or oncologists. There is evidence that poor semen quality, testicular cancer, undescended testes and hypospadias are symptoms of one underlying entity, testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is the result of disruption of embryonal programming and gonadal development during fetal life. An endocrine disrupter hypothesis to explain the adverse trends has been proposed. It is recommended that future epidemiological studies on trends in male reproductive health should not focus on one symptom alone, but be more comprehensive and take all aspects of TDS into account.

Cryptorchidism↗
PubMedDate not supplied

The role of follicle-stimulating hormone in spermatogenesis: lessons from knockout animal models.

The development of knockout mouse models for the FSH-beta subunit, the FSH receptor, and LH-receptor performed in different laboratories has confirmed and extended our knowledge concerning the critical role of these hormone-signaling systems in spermatogenesis. In this article, we summarize the phenotypic changes observed in male FSH receptor knockout (FORKO) mice. Young FORKO males have underdeveloped testis with 50% reduction in Sertoli cells, suggesting that FSH-R signaling is required very early for gonadal development, maturity, and function. These mice experience delayed puberty with postponement in the formation of round spermatids. Adult males show reduction in serum testosterone levels despite normal circulating LH concentration, indicating disturbances in Sertoli-Leydig cell communication. As a consequence of reduced sperm production and sperm quality, adult FORKO males have reduced fertility. Aberrant sperm from FORKO males have retention of cytoplasmic droplets and inadequate DNA compaction, hallmarks of infertility in many species including man. Interestingly, these changes are also experimentally inducible in FSH- and/or FSH-R-immunized male bonnet monkeys, creating a state of infertility. Reports of human mutations in FSH-beta and the FSH receptor also indicate that spermatogenesis is dependent on this system. Further investigations in FORKO males should be helpful in uncovering the downstream genes involved in sustaining Sertoli cell function and maintenance of the quantitative and qualitative aspects of spermatogenesis. This might pave the way for treatment of male infertility and contraception.

Amino Acid Substitution↗
PubMed1990

Effects of zeitgeber shifts on gonadal function in male domestic fowls.

Effects of shifting light dark (LD) schedule of 8 hr/week on comb height and gonadal development were investigated in male domestic fowls. Three-day-old birds were exposed to repeated delay (westward shift) or repeated advancement (eastward shift) of the LD schedule at weekly intervals till they attained the age of 20 weeks. Control birds were held in fixed LD 12:12 hr light/dark schedule. Comb height was monitored at weekly intervals beginning at the age of 7 weeks. At 12th, 16th and 20th week 5 birds from each schedule were sacrificed and gonadal volume was recorded. Results indicate that comb and gonadal growth were significantly higher in advance-schedule birds when compared with control and delay-schedule birds. Histologically, testes of advance-schedule birds were more active when compared with those of control and delay-schedule birds. It appears that the eastward shifts of the synchronizer schedule may exert stimulatory influence on gonads.

Animals↗
PubMed1997

What nature's knockout teaches us about GnRH activity: hypogonadal mice and neuronal grafts.

The hypogonadal mouse is one of "nature's knockouts," bearing a specific deletion in the gene for gonadotropin-releasing hormone (GnRH), with the result that no GnRH peptide is detectable in the brain. The lack of reproductive development after birth provides an animal model that has proved fruitful in clarifying the role of GnRH in reproductive behavior and physiology. Behavioral studies with hypogonadal mice convincingly demonstrate that although GnRH may facilitate the appearance of sexual behavior, this peptide is not essential for either male or female sexual behavior in the mouse. Administration of GnRH to hypogonadal mice with regimens mimicking GnRH pulsatility initiates reproductive development. Surprisingly, continuous exposure to GnRH stimulates remarkable ovarian and uterine growth and increased FSH release, although pituitary content of LH and FSH remains unchanged. In contrast, when brain grafts of normal fetal preoptic area (POA), containing GnRH cells, are implanted in the third ventricle of adult hypogonadal mice, both pituitary and plasma gonadotropin levels increase. Grafted GnRH neurons innervate the median eminence of the host and support pulsatile LH secretion in the majority of animals with graft-associated gonadal development. Studies of hypogonadal mice with POA grafts demonstrate that distinct components of reproductive function are dissociable: hosts may demonstrate reflex but not spontaneous ovulation; others may show positive but not negative feedback. Activation of grafted GnRH cells in response to sensory input to the host, as revealed in Fos expression studies, is an example of the integration of the graft with the host brain that underlies such capabilities. A goal of these studies is to elucidate the specific connectivity underlying discrete aspects of reproductive function.

Animals↗
PubMed2006

Expression analysis and evolutionary conservation of the mouse germ cell-specific D6Mm5e gene.

During our search for genes required for gonadal development and function in the mouse, we identified D6Mm5e (DNA segment, Chr 6. Miriam Meisler 5, expressed), a gene with an expression pattern highly restricted to the embryonic ovary and the postnatal testis. Based on RT-PCR, Northern blot, and in situ hybridization analyses, we show that D6Mm5e is expressed in the germ cells of the female embryo upon their initial entry into meiosis, and in male germ cells during the last stages of spermatogenesis. Two transcripts are detected in the gonads resulting from the alternative splicing of exon 8. This splicing event does not introduce a frame shift, and creates an mRNA product that uses the same stop codon as the longer transcript. Although D6Mm5e does not belong to any known protein family and does not contain any known protein signature motifs, the high level of evolutionary conservation and the cellular and temporal expression suggest that D6Mm5e may have a role in male and female gametogenesis. Here we report the gonad-restricted mRNA expression profile of D6Mm5e in the mouse, and the evolutionary conservation of its amino acid sequence.

Alternative Splicing↗
PubMed1995

Expression of neurotrophin receptors in the developing and adult testis.

Nerve growth factor (NGF) and the other members of the family of neurotrophic factors (the neurotrophin) are essential for neuronal development and differentiation. Neurotrophins interact with two types of cell surface receptors: a low-affinity receptor (p75 NGF-R) and a high-affinity tyrosine kinase receptor belonging to the trk proto-oncogene family, both expressed in the nervous system and in certain non-neuronal tissues. Recently, NGF immunoreactivity and mRNA have been detected in the testis of the adult mouse, rat and human. In the present report we demonstrate the expression of p75 NGF-R during early gonadal development, by mesenchymal cells of the embryonic mouse and rat testis. In the embryonic testis p75 NGF-R-positive cells are spread through the interstitial compartment; during postnatal development they become organized in a cellular layer that surrounds differentiating myoid cells of the seminiferous tubule. Our results also show the expression in the peripuberal and adult mouse and rat testis, of an abundant and shorter transcript of 3.2 kb that cross-hybridizes to the receptor mRNA (3.7 kb). This new mRNA species, which appears at the beginning of spermatogenesis, is expressed by pachytene spermatocytes and round spermatids.

Animals↗
PubMed2004

Aromatase modulation alters gonadal differentiation in developing zebrafish (Danio rerio).

This study investigated whether gonadal sex differentiation of zebrafish (Danio rerio) is susceptible to compounds that interfere with cytochrome P450 aromatase (P450arom). Treatment of zebrafish during the period of gonadal differentiation with either the non-steroidal aromatase inhibitor fadrozole or 17alpha-methyltestosterone (MT) changed gonad morphological differentiation and altered the pattern of P450arom gene (CYP19) expression. Application of fadrozole (500 microg/g of food) between days 35 and 71 post-fertilisation (pf) resulted in 100% masculinisation, i.e. the gonads of all individuals examined ( n = 40) showed testicular morphology. At the same time, fadrozole treatment suppressed gonadal CYP19A (gonad-derived CYP19 gene) mRNA expression, as assessed by means of semi-quantitative RT-PCR. After termination of fadrozole treatment at day 71 pf and subsequent rearing of zebrafish under control conditions until 161 days pf, the gonads of all individuals still displayed testicular morphology. Gonadal CYP19A expression, however, showed a dimorphic pattern, with 14 out of 22 individuals having low CYP19A mRNA levels similar to those found in testes of control fish, while eight fish showed high, ovary-like levels of gonadal CYP19A mRNA. MT treatment (10 microg/l) during the period of gonadal differentiation (days 35 to 71 pf) resulted in phenological feminisation, i.e., all fish examined (n = 28) showed an ovarian gonadal morphology. While gonadal CYP19A expression was suppressed compared to control fish, cerebral CYP19B (brain-derived CYP19 gene) mRNA expression was increased in 71-day-old MT-treated fish. The results from this study provide evidence that exogenous compounds interfering with the P450arom system are able to disrupt, even persistently, gonadal sex differentiation of the protogynic zebrafish.

Animals↗
PubMed1997

Predominant expression of a Z-chromosome-linked immunoglobulin superfamily gene, ZOV3, in steroidogenic cells of ovarian follicles and in embryonic gonads of chickens.

A cDNA clone, pZOV3, was isolated from the cDNA library of immature chicken ovaries and its gene was mapped to the middle of the short arm of the Z chromosome. The cDNA sequence suggests that ZOV3 is a novel member of the immunoglobulin superfamily. cDNA clones of homologues of chicken ZOV3 were also obtained from Japanese quail and pigeon. Northern blot hybridization suggests that the high-level expression of the ZOV3 gene is restricted to the gonads: embryonic, immature and mature ovaries, and embryonic and immature testes. Western blot analysis and immunocytological detection using specific polyclonal antibodies against amino- and carboxyl-terminal regions of ZOV3 demonstrate that ZOV3 is a plasma membrane-bound glycoprotein that exists in granulosa cells and islets of cells in the theca externa layer of ovarian follicles. The latter islets coincide with those producing estradiol-17 beta. In male and female embryos, production of ZOV3 is first prominent in medullary and seminiferous codes, respectively, of developing gonads. Then, after hatching, it is shifted to the cortex surrounding the primitive follicles in the ovary or is continued weakly in the primary seminiferous tubules in the testis. Expression of the ZOV3 gene and production of ZOV3 are no longer detectable in the mature testis. ZOV3 is unique among the immunoglobulin superfamily proteins in that it is produced predominantly in gonads. Its possible role in differentiation or maintenance of steroidogenic cells in an ovarian follicle is discussed.

Amino Acid Sequence↗
PubMed2006

Retinoid signaling determines germ cell fate in mice.

Germ cells in the mouse embryo can develop as oocytes or spermatogonia, depending on molecular cues that have not been identified. We found that retinoic acid, produced by mesonephroi of both sexes, causes germ cells in the ovary to enter meiosis and initiate oogenesis. Meiosis is retarded in the fetal testis by the action of the retinoid-degrading enzyme CYP26B1, ultimately leading to spermatogenesis. In testes of Cyp26b1-knockout mouse embryos, germ cells enter meiosis precociously, as if in a normal ovary. Thus, precise regulation of retinoid levels during fetal gonad development provides the molecular control mechanism that specifies germ cell fate.

Animals↗
PubMed2004

Differential actions of follistatin and follistatin-like 3.

Follistatin (FS) is an important physiological regulator of activin and other TGFbeta superfamily members. The recently discovered follistatin-like 3 (FSTL3; a.k.a. FLRG; FSRP) shares significant structural and functional homology with FS, but also has some interesting differences, including a prominent nuclear localization. The existence of these two related proteins allows detailed molecular and biochemical comparisons of the biologic roles of their individual structural elements. Current studies indicate that the heparin binding sequence is essential for the ability of FS to inhibit autocrine activin but is not sufficient to confer this activity on FSTL3. Preliminary analysis of FSTL3 transgenic mice suggests that FSTL3 regulates gonadal development and function through inhibition of the paracrine activity of activin and/or other related factors. These studies have identified important structural elements necessary for biological activity of FS and FSTL3 and potential roles for FSTL3 in vivo.

Animals↗