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PubMed2006

WT1 and glomerular diseases.

The WT1 gene encodes a zinc finger transcription factor involved in kidney and gonadal development and, when mutated, in the occurrence of kidney tumor and glomerular diseases. Patients with Denys-Drash syndrome present with early nephrotic syndrome with diffuse mesangial sclerosis progressing rapidly to end-stage renal failure, male pseudohermaphroditism, and Wilms' tumor. Incomplete forms of the syndrome have been described. Germline WT1 missense mutations located in exons 8 or 9 coding for zinc fingers 2 or 3 have been detected in nearly all patients with Denys-Drash syndrome and in some patients with isolated diffuse mesangial sclerosis. Patients with Frasier syndrome present with normal female external genitalia, streak gonads, XY karyotype and progressive nephropathy with proteinuria and nephrotic syndrome with focal and segmental glomerular sclerosis progressing to end-stage renal disease in adolescence or young adulthood. They frequently develop gonadoblastoma. Germline intronic mutations leading to the loss of the +KTS isoforms have been observed in all patients with Frasier syndrome. The same mutations have been observed in genetically female patients with isolated FSGS. Transmission of the mutation is possible. Frasier mutations have also been reported in children with Denys-Drash syndrome.

Child↗
PubMed2026

Ligand-based directed differentiation to produce granulosa-like cells expressing steroidogenic enzyme genes.

The ovarian granulosa cells are responsible for producing hormones and supporting oocytes through maturation and meiotic resumption. There is a need to generate granulosa-like cells (GLCs) from human induced pluripotent stem cells (hiPSCs) to better model human gonadal development and to test the effects of exogenous or pharmaceutical compounds on the ovary. Here we report a rapid ligand-based protocol for differentiating hiPSCs into cells that express markers of the transient developmental lineages and steroidogenic pathway genes. Single-cell RNA-sequencing (scRNA-seq) analysis identified canonical granulosa cell genes were expressed in a subset of cells and identified new genes of interest that were significantly associated with computationally modeled pseudotime. HSD17B1 was expressed in resulting GLCs but at low levels, suggesting an immature granulosa cell phenotype. The GLCs were produced using a simple culture method that could be augmented for granulosa cell functions such as sustaining oocyte growth. Producing GLCs through protocols such as this one is a first step toward designing large-scale ovarian endocrinology assays and developing personalized cell-based fertility and hormone restoration technologies in the future. This rapid protocol produced cells that express steroidogenic enzyme genes etoc blurb. Kubo and colleagues present a 5-day rapid protocol to generate immature granulosa-like cells from hiPSCs. Cells differentiated with inhibition of DKK1, a WNT signaling target gene, expressed gonadal ridge markers and FOXL2 transcripts and protein. Additionally, steroidogenic enzyme genes were expressed. A small population of differentiated cells were identified as expressing early-stage granulosa cell genes by single-cell RNA-seq.

Female↗
PubMedDate not supplied

Genetic studies in varicocele infertility: I: pedigree, nuclear sex and seminal nucleic acids.

The hereditary predisposition of varicocele men to develop infertility was investigated in a controlled study involving 30 infertile varicocele patients. Analysis of the pedigree charts, determination of sex chromatin constitution, and biochemical measurement of seminal nucleic acid (DNA/RNA) were undertaken. Sibs and Kins of infertile varicocele patients showed various developmental anomalies particularly of the genito-crural area. cocele formation while the gonads develop in the normal line. Such condition may be represented in fertile men with clinically detectable varicocele. In addition, the postulated defective gene in VI patients may interfere as well with the normal development of the mesenchyme-derived interstitial cells of Leydig. Defective testicular steroid hormone biosynthesis thus obtained may explain the reported decrease in androgen level in peripheral blood, sexual impotentia and accessory genital gland dysfunction (Raboch and Starka - 1971; Comhaire and Vermeulen - 1975). Moreover, being androgen dependent (Lacy - 1973), spermatogenesis may display abnormal patterns due to lowered intratesticular androgen concentration (Rodriguez-Rigau et al. - 1978). The outcome and severity of spermatogenic derangement may depend partially on the severity of disordered androgen biosynthesis. The present work showed significant decrease in sperm count, motility, normal forms and nucleic acid content (DNA and RNA) of the seminal fluid in VI patients. The decrease in the amount of DNA per millilitre of seminal fluid in VI patients may be explained by the decrease in sperm population (oligozoospermia). The decrease in the amount of RNA per millilitre of seminal fluid in VI patients may be due to the total decrease in cellular content of the seminal fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Neural transplantation in hypogonadal (hpg) mice - physiology and neurobiology.

The hypogonadal (hpg) mouse mutant has a deletion in the region encoding the hypothalamic gonadotrophic hormone-releasing hormone decapeptide. As a consequence pituitary gonadotrophic hormone synthesis and release is severely curtailed and there is little or no post-natal gonadal development. Grafts of late fetal/early neonatal brain tissue containing the decapeptide-producing neurones into the third ventricle of hpg mice result, in a majority of animals, in a near normalisation of pituitary function with full spermatogenesis in male mice and full follicular and uterine development in females. The vast majority of positive responding females with vaginal opening and uterus growth show no evidence of spontaneous oestrous cycles, ovulation or corpora lutea. These female mice mate with normal males with many of them demonstrating reflex ovulation. In both male and female mutants with successful grafts there is an absence of gonadal steroid negative feedback upon the synthesis and secretion of pituitary gonadotrophic hormones. The releasing factor axon terminals from grafts within the third ventricle identified by immunohistochemical methods are targeted specifically to the median eminence. There is evidence for host innervation of grafts, but how specific this is for the control of gonadotrophic hormone-releasing hormone cell bodies remains to be elucidated.

Animals↗
PubMed1994

The role of nuclear receptors in steroid hormone production.

Epidemiological studies implicate steroid hormones as important factors in the development of neoplasia, and hormonal manipulation constitutes an important treatment arm in cancer therapy. Recent studies demonstrate a key role for nuclear receptor proteins in the expression of genes encoding the cytochrome P450 enzymes responsible for steroid hormone biosynthesis. Two orphan nuclear receptors, SF-1 and NGFI-B, regulate steroid hydroxylase transcription; the gene encoding SF-1 is also essential for adrenal and gonadal development. These results highlight the importance of specific nuclear receptors in regulating the enzymes that make essential steroid hormones and in the differentiation of the primary steroidogenic tissues. Ultimately, these nuclear receptors may provide new targets for the design of novel therapies for hormone-dependent cancers.

Adrenal Cortex Hormones↗
PubMed2006

Molecular cloning of the rice field eel Nup93 with predominant expression in gonad and kidney.

Nucleoporins (Nups) are important components of nuclear pore complexes (NPCs). NPCs control gene expression, cells proliferation and differentiation by mediating exchange of cellular signal molecules on both nuclear and cytoplasmic sides. Using subtractive screening, 3'end fragment of Nup93 from the testis cDNA library of the rice field eel was obtained. Full-length cDNA of the gene was further cloned by degenerate PCR and 5'RACE methods. Sequence analysis indicated that the homology of the rice field eel Nup93 were 36.5% with yeast Nic96, 94.6% and 90.5% with Nup93 of zebrafish and human, respectively. Phylogenetic analysis showed that the rice field eel Nup93 fits with Nup93 of the other fishes. Real-time PCR result showed that expression of Nup93 in gonads and kidney were much higher than in other tissues, and different expression quantities among gonads of three sexes were also observed, suggesting that Nup93 may involve in gonad development.

Amino Acid Sequence↗
PubMed2000

Permanent and functional male-to-female sex reversal in d-rR strain medaka (Oryzias latipes) following egg microinjection of o,p'-DDT.

Complete sex reversal of fish is accomplished routinely in aquaculture practices by exposing fish to exogenous sex steroids during gonadal differentiation. A variety of environmental chemicals are also active at sex steroid receptors and theoretically possess the potential to alter normal sexual differentiation in fish. However, in controlled environmental chemical exposures to date, only partial alterations of fish sexual phenotype have been observed. Here we report complete, permanent, and functional male-to-female sex reversal in the Japanese medaka (Oryzias latipes, d-rR strain) after a onetime embryonic exposure to the xenoestrogen o, p'-DDT. d-rR strain medaka are strict gonochorists that possesses both sex-linked pigmentation, which distinguishes genotypic sex, and sexually dimorphic external secondary sexual characteristics, which distinguish phenotypic sex. We directly microinjected the xenoestrogen o, p'-DDT into the egg yolks of medaka at fertilization to parallel the maternal transfer of lipophilic contaminants to the embryo. At 10 weeks of age, microinjected medaka were examined for mortality and sex reversal. A calculated embryonic dose of 511 +/- 22 ng/egg o, p'-DDT (mean +/- standard error) resulted in 50% mortality. An embryonic exposure of 227 +/- 22 ng/egg o, p'-DDT resulted in 86% (6 of 7) sex reversal of genetic males to a female phenotype (XY females). XY females were distinguished by sex-linked male pigmentation accompanying female secondary sexual characteristics. Histologic examination of the gonads confirmed active ovaries in 100% of the XY females. In 10-day breeding trials in which XY females were paired with normal XY males, 50% of the XY females produced fertilized embryos; this represents a comparable breeding success rate to normal XX females. Fertilized eggs produced from XY females hatched to viable larvae. These results clearly indicate that a weakly estrogenic pesticide, o, p'-DDT, when presented during the critical period of gonadal development, can profoundly alter sexual differentiation.

Animals↗
PubMed1997

Role of androgens in testicular tumor development in inhibin-deficient mice.

To understand gonadal tumor development, we have previously created a mouse model in which mice deficient in the inhibins develop gonadal sex cord-stromal tumors with essentially 100% penetrance. These tumors develop as early as 4 weeks of age and cause cancer cachexia-like symptoms and subsequent death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice eventually develop adrenal cortical tumors with nearly 100% penetrance. These studies have identified inhibin as a novel secreted tumor suppressor protein with specificity for the gonads and adrenal glands. Sex steroids have been implicated to influence gonadal tumor development in humans and mice. To determine the role of androgens in gonadal tumorigenesis in inhibin-deficient male mice, we have used a genetic intercross strategy, breeding inhibin alpha mutant mice with tfm (testicular feminization, a naturally occurring androgen receptor mutant) carrying females to eventually generate compound mutant male mice that lack inhibins and carry the tfm mutation. These compound mutant mice, like inhibin-deficient mice, continue to develop testicular tumors and the accompanying cancer cachexia-like wasting syndrome. Consistent with these findings, elevated levels of activins A and B secreted from the gonadal tumors are seen in the adult compound mutant mice as well as the secondary pathological consequences of these high activin levels in the livers and glandular stomachs. However, in contrast to male mice lacking only inhibin, in which essentially 100% of the testicular tumors are hemorrhagic, 65% of the tumors in these compound mutant male mice are less hemorrhagic, and approximately 50% of the compound mutants live longer than 17 weeks of age (95% of the male mice lacking only inhibin die by 12 weeks). These results suggest that androgens are not required for testicular tumor development in inhibin-deficient mice, but may play a regulatory role in testicular tumor progression.

Activins↗
PubMed2006

Parasites of winter flounder (Pleuronectes americanus) as an additional bioindicator of stress-related exposure to untreated pulp and paper mill effluent: a 5-year field study.

A study was conducted in a marine inlet to assess the effects of untreated discharges from a pulp and paper mill, a municipality, and industries in western Newfoundland on winter flounder (Pleuronectes americanus), a fish species shown previously to be sensitive to environmental contaminants in sediment. The fish were captured by SCUBA divers about 2 km down-current from the mill discharging effluent containing resin acids, and at three reference sites 2 to 11 km away near the opposite shore, each spring in five consecutive years and the fish were necropsied on site. A total of 360 and 339 flounder were examined near the mill and references sites, respectively. Several bioindicators were used to assess fish health including parasites. More fish exhibiting external and microscopic lesions in several tissues, lower condition factors, elevated hepatosomatic index, and delayed reproductive development were observed in samples taken near the paper mill than at the reference sites. A higher prevalence of an ectoparasite, Cryptocotyle lingua, but a significantly lower mean abundance of three metazoans infecting the digestive tract was noted in fish near the mill than in the reference samples. These results, comprising abnormal fish size distribution, low body condition factor, external and internal lesions, enlarged liver, delayed gonadal development, and changes in parasitism, were stress-related, indicative of impaired health, and associated primarily with untreated discharges from the pulp and paper mill. This integrated and multidisciplinary study also provides further evidence on the use of fish parasites as a valid and an additional bioindicator in programs monitoring environmental contaminants.

Analysis of Variance↗
PubMed2004

The sys-1 and sys-3 genes cooperate with Wnt signaling to establish the proximal-distal axis of the Caenorhabditis elegans gonad.

To form the proximal-distal axis of the C. elegans gonad, two somatic gonadal precursor cells, Z1 and Z4, divide asymmetrically to generate one daughter with a proximal fate and one with a distal fate. Genes governing this process include the lin-17 frizzled receptor, wrm-1/beta-catenin, the pop-1/TCF transcription factor, lit-1/nemo-like kinase, and the sys-1 gene. Normally, all of these regulators promote the distal fate. Here we show that nuclear levels of a pop-1 GFP fusion protein are less abundant in the distal than in the proximal Z1/Z4 daughters. This POP-1 asymmetry is lost in mutants disrupting Wnt/MAPK regulation, but retained in sys-1 mutants. We find that sys-1 is haplo-insufficient for gonadogenesis defects and that sys-1 and pop-1 mutants display a strong genetic interaction in double heterozygotes. Therefore, sys-1 is a dose-sensitive locus and may function together with pop-1 to control Z1/Z4 asymmetry. To identify other regulatory genes in this process, we screened for mutants resembling sys-1. Four such genes were identified (gon-14, -15, -16, and sys-3) and shown to interact genetically with sys-1. However, only sys-3 promotes the distal fate at the expense of the proximal fate. We suggest that sys-3 is a new key gene in this pathway and that gon-14, gon-15, and gon-16 may cooperate with POP-1 and SYS-1 at multiple stages of gonad development.

Animals↗
PubMed2001

The one-to-four rule and paralogues of sex-determining genes.

Because of two successive rounds of tetraploidization at their inception, the vertebrates contain four times more protein-coding genes in their genome than the invertebrates: 60,000 vs. 15,000. Consequently, each invertebrate gene has been amplified to the maximum of four paralogous genes in vertebrates: the one-to-four rule. When this rule is applied to genes pertinent to gonadal development and differentiation, the following emerged: (i) Two closely related zinc-finger transcription factor genes in invertebrates have been amplified to two paralogous groups in vertebrates. One consisted of EGR1, EGR2, EGR3 and EGR4, whereas the only known paralogue of the other is WT1, which controls the developmental fate of the entire nephric system, and therefore of gonads. Interestingly, EGR1 and WT1 act as antagonists of each other in nephroblastic cells. (ii) SF-1, which controls the fate of two steroid hormone-producing organs, adrenals and gonads, is descended from the invertebrate Ftz-F1 gene, and its only known paralogue is GCNF-1. (iii) The Y-linked SRY, the mammalian testis-determining gene, is a paralogue neither of SOX3 (SRX) nor of SOX9. Its ancient origin suggests that SRY once became extinct in earlier vertebrates, only to revive itself in the mammalian ancestor. (iv) Inasmuch as four paralogues of one invertebrate nuclear receptor gene have differentiated to receptors of androgen, mineralocorticoid, glucocorticoid and progesterone, there should at most be four paralogous estrogen-receptor genes in the vertebrate genome. It is likely that one of them plays a pivotal role in the estrogen-dependent sex-determining mechanism so commonly found among reptiles, amphibians and fish.

Animals↗
PubMed1999

The one-to-four rule and paralogues of sex-determining genes.

Because of two successive rounds of tetraploidization at their inception, the vertebrates contain four times more protein-coding genes in their genome than the invertebrates: 60,000 versus 15,000. Consequently, each invertebrate gene has been amplified to the maximum of four paralogous genes in vertebrates: the one-to-four rule. When this rule is applied to genes pertinent to gonadal development and differentiation, the following emerged: (i) Two closely related zinc-finger transcription factor genes in invertebrates have been amplified to two paralogous groups in vertebrates. One consisted of EGR1, EGR2, EGR3 and EGR4, whereas the only known paralogue of the other is WT1, which controls the developmental fate of the entire nephric system, and therefore of gonads. Interestingly, EGR1 and WT1 act as antagonists of each other in nephroblastic cells. (ii) SF-1, which controls the fate of two steroid hormone-producing organs, adrenals and gonads, is descended from the invertebrate Ftz-F1 gene, and its only known paralogue is GCNF-1. (iii) The Y-linked SRY, the mammalian testis-determining gene, is a paralogue neither of SOX3 (SRX) nor of SOX9. Its ancient origin suggests that SRY once became extinct in earlier vertebrates, only to revive itself in the mammalian ancestor. (iv) Inasmuch as four paralogues of one invertebrate nuclear receptor gene have differentiated to receptors of androgen, mineralocoticoid, glucocorticoid and progesterone, there should at most be four paralogous estrogen-receptor genes in the vertebrate genome. It is likely that one of them plays a pivotal role in the estrogen-dependent sex-determining mechanism so commonly found among reptiles, amphibians and fish.

Adrenal Cortex↗
PubMed1986

The culture of Diplostomum spathaceum metacercariae on the chick chorioallantois.

Metacercariae (2,828) obtained from the lens of naturally infected Aplodinotus grunniens were transplanted onto chorioallantoic membranes (CAM's) of 94 eggs (means 30/egg) 5 to 12 days old. Membranes were examined 2 to 8 days later and 381 flukes were recovered. Two hundred fifty-nine chorioallantoic-grown worms were transferred to 28 additional embryos 3 to 8 days after the initial inoculation. These eggs were examined 3 to 11 days later. Fifty-three serially transferred worms were recovered after 7 to 14 days on CAM's. Six stages of development were recognized: stage 1, immature; stage 2, genital rudiment; stage 3, testes; stage 4, follicular ovary; stage 5, vitellaria; stage 6, ovigerous. The intestinal ceca of many worms (except stage 1) contained ingested blood. Trematode eggs oviposited on CAM's were embryonated in tap water, and viable miracidia were observed in 15. No previous study has achieved gonadal development in Diplostomum spathaceum on the CAM. Furthermore, inasmuch as metacercaria matured and produced fertile eggs, this form is shown to be a useful model for the study of trematode differentiation. The development of metacercariae to ovigerous adults capable of producing viable miracidia suggests that the CAM shares characteristics with the intestine of the definitive host, a piscivorous bird.

Allantois↗
PubMed1998

Gscl, a gene within the minimal DiGeorge critical region, is expressed in primordial germ cells and the developing pons.

Gscl, a paired-type homeobox gene, has been implicated in the pathology of DGS/VCFS by virtue of its genomic location and its structural similarity to the Gsc gene family. Immunohistochemical and in situ studies were performed to examine the expression pattern of this gene during embryonic development. A polyclonal antibody, generated to the full-length protein and shown to be specific for GSCL by both Western blotting and immunofluorescence, was used for immunohistochemical localization. Both in situ and antibody staining localized GSCL expression to a cluster of cells in the pons region of the developing brain. This GSCL expression pattern showed partial overlap with that of Pax6. More detailed immunohistochemistry revealed the GSCL in primordial germ cells during migration from the epithelium of the hindgut and later as they colonize the developing gonads. GSCL was not detected in tissues affected in DGS/VCSF.

3T3 Cells↗
PubMed2006

Mice mutant in the DM domain gene Dmrt4 are viable and fertile but have polyovular follicles.

Proteins containing the DM domain, a zinc finger-like DNA binding motif, have been implicated in sexual differentiation in diverse metazoan organisms. Of seven mammalian DM domain genes, only Dmrt1 and Dmrt2 have been functionally analyzed. Here, we report expression analysis and targeted disruption of Dmrt4 (also called DmrtA1) in the mouse. Dmrt4 is widely expressed during embryonic and postnatal development. However, we find that mice homozygous for a putative null mutation in Dmrt4 develop essentially normally, undergo full sexual differentiation in both sexes, and are fertile. We observed two potential mutant phenotypes in Dmrt4 mutant mice. First, ovaries of most mutant females have polyovular follicles, suggesting a role in folliculogenesis. Second, 25% of mutant males consistently exhibited copulatory behavior toward other males. We also tested potential redundancy between Dmrt4 and two other gonadally expressed DM domain genes, Dmrt1 and Dmrt7. We observed no enhancement of gonadal phenotypes in the double mutants, suggesting that these genes function independently in gonadal development.

Animals↗
PubMed2000

Partially deleted SRY gene confined to testicular tissue in a 46,XX true hermaphrodite without SRY in leukocytic DNA.

True hermaphroditism is an uncommon form of intersexuality in which testicular and ovarian tissue develop in the same individual. Most true hermaphrodites are 46,XX and lack SRY, the testis-determining gene. We describe results of molecular studies performed in a 46,XX true hermaphrodite SRY-negative in DNA from blood leukocytes but SRY-positive in DNA obtained from the testicular portion of the ovotestis. Surprisingly, the SRY identified in gonadal DNA carries a partial deletion at the 5' end of the gene. Our patient is the first case of a naturally occurring deletion within the SRY ORF (with a normal HMG box) and provides a new explanation for the abnormal gonadal development observed in 46,XX true hermaphrodites.

DNA↗
PubMed2005

Intersex in wild roach (Rutilus rutilus) from Danish sewage effluent-receiving streams.

Roach (Rutilus rutilus) from Danish streams that receive discharges of domestic sewage effluent were examined for the presence of alterations to gonadal development. In male roach, intersex was observed at a prevalence of 4.5-5% at reference sites and 6.7-6.5% at sewage effluent-impacted sites. A positive correlation was found between sewage effluent load and intersex frequency among male roach. The highest frequency of intersex (26.5%) was found in the stream Kristrup Landkanal, which had the highest percentage and load of sewage effluent (87,578 population equivalents). Further, a tendency to an average higher severity of the phenomenon (calculated as an intersex index value) was seen in males from streams impacted by sewage effluent compared to males from reference sites. However, this was significant only in male fish from Egaa Brook. Among roach from the Kristrup Landkanal 5.8% of male and 0.8% of female roach were infected with the parasite Pleistophora mirandellae, causing degenerative changes in testes and ovaries. No correlation was seen between the intersex condition and the presence of P. mirandellae in the gonads of roach.

Animals↗
PubMed2001

Stanniocalcin gene expression during mouse urogenital development: a possible role in mesenchymal-epithelial signalling.

Stanniocalcin (STC) is a polypeptide hormone first discovered in fish and more recently in mammals. In mammals, the STC gene is widely expressed and the hormone is involved in a variety of functions, but STC does not normally circulate in the blood. In both kidney and gut, STC regulates phosphate fluxes across the transporting epithelia, whereas in brain it protects neurons against cerebral ischemia and promotes neuronal cell differentiation. However, the gene is most highly expressed in ovary and expression is dramatically up-regulated by both pregnancy and nursing. STC mRNA levels are also high in the developing mouse embryo, but literally nothing is known of the tissue pattern of gene expression. Therefore, the aim of this study was to map the temporal and spatial patterns of gene expression during mouse embryologic development, starting with the urogenital system where the gene is so highly expressed in adults. STC mRNA was evident as early as E10.5 in both the mesonephros and genital ridge. Between E10.5 and 14.5 in developing kidney, STC was produced in undifferentiated mesenchyme cells and sequestered by ureteric bud epithelial cells that did not express the gene but nonetheless contained high levels of STC protein. Thereafter, the distribution pattern resembled that in adults such that gene expression predominated in collecting duct cells, whereas protein was present in most nephron segments. The pattern of gene expression during gonadal development was sexually dimorphic. In males, expression was first evident on E12.5 in interstitial mesenchyme cells surrounding the developing sex cords, whereas the protein accumulated in developing gonocytes within the sex cords that did not express the gene. This pattern became more pronounced over the course of gestation. In contrast, ovarian gene expression was only weakly evident during development. Collectively, the evidence suggests that in addition to its regulatory effects in adults, STC has novel and distinctive roles in the mesenchymal-epithelial interactions that are vital to normal organogenesis.

Animals↗