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Carlo Foresta - One of the best experts on this subject based on the ideXlab platform.
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Effects of endocrine disruptors on fetal Testis Development, male puberty, and transition age
Endocrine, 2020Co-Authors: Francesco Cargnelutti, Andrea Di Nisio, Francesco Pallotti, Iva Sabovic, Matteo Spaziani, Maria Grazia Tarsitano, Donatella Paoli, Carlo ForestaAbstract:Purpose Endocrine disruptors (EDs) are exogenous substances able to impair endocrine system; consequently, they may cause numerous adverse effects. Over the last years, particular focus has been given to their harmful effects on reproductive system, but very little is known, especially in males. The aim of this review is to discuss the detrimental effects of EDs exposure on fetal Testis Development, male puberty, and transition age. Methods A search for the existing literature focusing on the impact of EDs on fetal Testis Development, male puberty, andrological parameters (anogenital distance, penile length, and testicular volume), and testicular cancer with particular regard to pubertal age provided the most current information available for this review. Human evidence-based reports were given priority over animal and in vitro experimental results. Given the paucity of available articles on this subject, all resources were given careful consideration. Results Information about the consequences associated with EDs exposure in the current literature is limited and often conflicting, due to the scarcity of human studies and their heterogeneity. Conclusions We conclude that current evidence does not clarify the impact of EDs on human male reproductive health, although severe harmful effects had been reported in animals. Despite controversial results, overall conclusion points toward a positive association between exposure to EDs and reproductive system damage. Further long-term studies performed on wide number of subjects are necessary in order to identify damaging compounds and remove them from the environment.
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Effects of endocrine disruptors on fetal Testis Development, male puberty, and transition age.
Endocrine, 2020Co-Authors: Francesco Cargnelutti, Andrea Di Nisio, Francesco Pallotti, Iva Sabovic, Matteo Spaziani, Maria Grazia Tarsitano, Donatella Paoli, Carlo ForestaAbstract:Endocrine disruptors (EDs) are exogenous substances able to impair endocrine system; consequently, they may cause numerous adverse effects. Over the last years, particular focus has been given to their harmful effects on reproductive system, but very little is known, especially in males. The aim of this review is to discuss the detrimental effects of EDs exposure on fetal Testis Development, male puberty, and transition age. A search for the existing literature focusing on the impact of EDs on fetal Testis Development, male puberty, andrological parameters (anogenital distance, penile length, and testicular volume), and testicular cancer with particular regard to pubertal age provided the most current information available for this review. Human evidence-based reports were given priority over animal and in vitro experimental results. Given the paucity of available articles on this subject, all resources were given careful consideration. Information about the consequences associated with EDs exposure in the current literature is limited and often conflicting, due to the scarcity of human studies and their heterogeneity. We conclude that current evidence does not clarify the impact of EDs on human male reproductive health, although severe harmful effects had been reported in animals. Despite controversial results, overall conclusion points toward a positive association between exposure to EDs and reproductive system damage. Further long-term studies performed on wide number of subjects are necessary in order to identify damaging compounds and remove them from the environment.
Michael K. Skinner - One of the best experts on this subject based on the ideXlab platform.
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effect of the anti androgenic endocrine disruptor vinclozolin on embryonic Testis cord formation and postnatal Testis Development and function
Reproductive Toxicology, 2004Co-Authors: Mehmet Uzumcu, Hiroetsu Suzuki, Michael K. SkinnerAbstract:Abstract Vinclozolin is a systemic dicarboximide fungicide that is used on fruits, vegetables, ornamental plants, and turf grass. Vinclozolin and its metabolites are known to be endocrine disruptors and act as androgen receptor antagonists. The hypothesis tested in the current study is that transient embryonic exposure to an anti-androgenic endocrine disruptor at the time of Testis determination alters Testis Development and subsequently influences adult spermatogenic capacity and male reproduction. The effects of vinclozolin on embryonic testicular cord formation in vitro were examined, as well as the effects of transient in utero vinclozolin exposure on postnatal Testis Development and function. Embryonic day 13 (E13, sperm-positive vaginal smear day = E0) gonads were cultured in the absence or presence of vinclozolin (50–500 μM). Vinclozolin treated gonads had significantly fewer cords (P
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effect of transient embryonic in vivo exposure to the endocrine disruptor methoxychlor on embryonic and postnatal Testis Development
Journal of Andrology, 2003Co-Authors: Andrea S. Cupp, Mehmet Uzumcu, Hiroetsu Suzuki, Kristen A Dirks, Brigette Phillips, Michael K. SkinnerAbstract:The current study was designed to examine the effects of a transient embryonic exposure to the pesticide methoxychlor, an endocrine disruptor, on in vivo rat Testis Development and function. Gestating female rats were transiently administered methoxychlor (MXC) from embryonic day 7 (E7; EO = plug date) through E15. Embryonic testes were collected at E16 and postnatal (PO = day of birth) testes at P4, P10, P17-20, and P60. Seminiferous cords formed in testes from MXC exposed males. However, at E16, there was a decrease in the area of cords and an increase in interstitial area in MXC exposed testes when compared with controls. At all postnatal ages collected, there did not appear to be differences in seminiferous cord/tubule area, interstitial area, or number of seminiferous cords/tubules between untreated controls and males exposed to MXC. Exposure to the endocrine disruptor also had no effect on the postnatal organ weights of a variety of different organs, nor were testosterone levels altered. Interestingly, there were reductions in the number of germ cells in testes from MXC-exposed males at P17-P20 when compared with untreated controls. Furthermore, there was a twofold increase in apoptotic cells in tubules from pubertal P17-P20-MXC exposed males when compared with untreated controls. Testes were collected from adult P60 males to determine if early embryonic and postnatal alterations in germ cell numbers or Testis cellular composition had compromised spermatogenesis. In adult P60 MXC exposed testes there were no gross morphological changes in Testis structure or cellular composition over that of controls. However, there was an increase in apoptotic cell number in elongating spermatids in MXC exposed testes. Four P60 males that were exposed to MXC during gestation and 4 control males were bred with unexposed females to determine their ability to produce offspring. All MXC exposed males were capable of impregnating females and had normal litter size and pup weights. Combined observations demonstrated that exposure to MXC during gestation at a critical stage of Testis Development (ie, sex determination) affects embryonic Testis cellular composition, germ cell numbers, and germ cell survival. While alterations in these parameters does not affect the ability of males to produce offspring, there appears to be a reduced spermatogenic capacity associated with MXC treatment. Therefore, transient embryonic exposure to an endocrine disruptor (methoxychlor) during gestation can influence the germline and fertility in adult males.
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Expression and Action of Neurotropin-3 and Nerve Growth Factor in Embryonic and Early Postnatal Rat Testis Development
Biology of reproduction, 2000Co-Authors: Andrea S. Cupp, Grace Kim, Michael K. SkinnerAbstract:The current study examines the expression and potential actions of neurotropin-3 (NT3), nerve growth factor (NGF), and their receptors during morphological sex determination (seminiferous cord formation) and perinatal rat Testis Development. The expression of neurotropins and their receptors was analyzed with immunohistochemistry. Cellular localization of neurotropin ligand and receptor proteins changed during embryonic Testis Development. Neurotropin-3 was localized to Sertoli cells at Embryonic Day 14 (E14), was present in gonocytes at Postnatal Day 0 (P0), and after birth became localized to the interstitium and Sertoli cells (P3‐P5). The expression of trk C (the high affinity receptor for NT3) was localized to mesonephric ducts and cells surrounding the cords (E14‐E18). In addition, Sertoli cells and preperitubular cells surrounding the cords at E14 also stained for trk C. Neurotropin-3 was expressed in gonocytes and Sertoli cells at P0‐P5. Nerve growth factor was detected in Sertoli cells at E14, was clearly in Sertoli and interstitial cells at E16 and E18, and in Sertoli, germ, and interstitial cells from P0‐P5. The expression of trk A (the high affinity receptor for NGF) was located in Sertoli and interstitial cells at E16‐P5. To determine the actions of neurotropins during embryonic and perinatal Testis Development, experiments were conducted on E13 and P0 Testis. Antisense oligonucleotide experiments with NT3 were used on E13 Testis organ cultures to determine effects on seminiferous cord formation. Cord formation was inhibited in 40% of the organ cultures treated with the antisense NT3 oligonucleotides, while no inhibition was observed with sense oligonucleotides. In P0 Testis cultures, both NT3 and NGF alone and in combination stimulated thymidine incorporation into DNA. Therefore, the neurotropins are involved in embryonic morphological events (cord formation; NT3) and in growth of the perinatal Testis (P0; NT3 and NGF). To define further the growth effects of neurotropins on Testis Development, expression of transforming growth factor alpha and beta (TGFa and TGFb) were examined in response to neurotropins. The P0 Testis cultures were treated with neurotropins, and expression of mRNA for TGFa and TGFb was analyzed utilizing a quantitative reverse transcription-polymerase chain reaction assay. Nerve growth factor and NT3 alone or in combination inhibited expression of mRNA for TGFa while NT3 increased mRNA expression of epidermal growth factor receptor. The combination treatment of neurotropins inhibited expression of TGFb1 and increased expression of TGFb3. In summary, observations suggest that NT3, NGF, trk A, and trk C are localized to cells critical to seminiferous cord formation and appear to be important regulators of morphological sex determination. In addition to these morphological effects, both NT3 and NGF stimulate P0 Testis growth and may elicit their action through altering the expression of locally produced growth fac
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Expression and Action of Transforming Growth Factor Beta (TGFβ1, TGFβ2, and TGFβ3) during Embryonic Rat Testis Development
Biology of reproduction, 1999Co-Authors: Andrea S. Cupp, Grace Kim, Michael K. SkinnerAbstract:The objective of the current study was to determine the role of transforming growth factor beta (TGFb) during seminiferous cord formation and embryonic Testis Development. The expression pattern of mRNA for TGFb isoforms was evaluated during Testis Development through a quantitative reverse transcriptionpolymerase chain reaction (QRT-PCR) procedure. Expression of mRNA for TGFb1 was highest at postnatal day 0 (P0) and P10. In contrast, TGFb2 was high at embryonic day 15 (E15), declined at E16, and showed a transient increase at P0 through P3 of Testis Development. Interestingly, expression of mRNA for TGFb3 was high during embryonic Development and then declined after P3. Immunohistochemical localization of TGFb1 and TGFb2 demonstrated expression in Sertoli cells at E14 and in the seminiferous cords at P0. Selective interstitial cells expressed high concentrations of TGFb1 and TGFb2 in P0 Testis. TGFb3 was expressed in selective cells at the junction of the E14 Testis and mesonephros. The cells expressing TGFb 3i n the Testis appeared to be preperitubular cells that resided around the seminiferous cords. TGFb3 was localized to gonocytes in P0 Testis. TGFb1 was found to have no influence on seminiferous cord formation in embryonic organ cultures of E13 Testis. In contrast, growth of both E13 and E14 embryonic organ cultures was inhibited by TGFb1 and resulted in reduced Testis size (40% of controls) with fewer cords present. A P0 Testis cell culture and thymidine incorporation assay were used to directly examine the effects of recombinant TGFb1. TGFb1 alone had no influence on thymidine incorporation in P0 Testis cell cultures when compared to controls. Interestingly, TGFb1 inhibited epidermal growth factor (EGF), and 10% calf serum stimulated P0 Testis cell growth but not FSH-stimulated growth. Therefore, TGFb1 appears to inhibit Testis growth in both the embryonic and early postnatal periods. The hormonal regulation of TGFb expression was measured using P0 Testis cell cultures and a QRTPCR procedure for each TGFb isoform. High concentrations of EGF stimulated expression of mRNA for TGFb1 after 24 h but suppressed expression of TGFb3. In contrast, there was no effect of FSH on TGFb isoform expression. In summary, TGFb regulates embryonic and P0 Testis growth through inhibiting the actions of positive growth factors such as EGF. In addition, EGF but not FSH appears to regulate TGFb isoform expression. Combined observations from the present study demonstrate that TGFb isoforms are differentially expressed and appear to be regulators of Testis growth during the embryonic and early postnatal periods.
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Action of retinoids on embryonic and early postnatal Testis Development
Endocrinology, 1999Co-Authors: Andrea S. Cupp, Grace Kim, Michael K. Skinner, Jannette M. Dufour, Kwan Hee KimAbstract:The current study investigates the hypothesis that retinoids have a role in embryonic Testis Development. The action of retinoids on Testis Development and the expression of retinoic acid receptors (RAR alpha, RAR beta, RAR gamma) were examined. In embryonic day 13 (E13; plug date = E0) Testis organ cultures an RAR-selective agonist and all-trans retinoic acid completely inhibited seminiferous cord formation. In contrast, an RAR alpha-selective antagonist had no effect. RT-PCR demonstrated that RAR alpha messenger RNA (mRNA) was expressed at all Developmental time points evaluated, which included embryonic day 14 (E14) through postnatal day 30 (P30). Expression of RAR beta mRNA was present at E15 through P2, whereas RAR gamma mRNA was expressed at E18 through P2. Cellular localization of receptors by immunohistochemistry indicated that RAR alpha was localized to the interstitium at E18 and to the seminiferous cords by P0. RAR beta and RAR gamma were detected in both interstitium and cords at E16 and by E18 were mainly expressed in the cords. At P0 RAR beta and RAR gamma were localized to the germ cell populations. To examine retinoid actions, the growth of P0 Testis cultures were investigated. Interestingly, retinol and retinoic acid did not inhibit growth of P0 Testis cultures but did inhibit the action of growth stimulators. Retinoic acid inhibited FSH, EGF, and 10% calf serum stimulated growth in P0 Testis cultures. The hypothesis tested was that the inhibitory effects of retinoids on P0 Testis growth may be mediated through the growth inhibitor, transforming growth factor-beta (TGF beta). The action of retinoids on TGF beta mRNA expression was examined in P0 Testis cultures. Retinoic acid stimulated TGFbeta3 mRNA expression within 24 h and increased expression of TGFbeta1 and TGFbeta2 after 72 h. Retinol increased expression of TGFbeta1 and TGFbeta2 but not TGFbeta3 after 72 h of treatment. These observations indicate that retinoic acid can influence seminiferous cord formation and Testis growth. The inhibitory actions of retinoids may in part be mediated through increased expression of TGFbeta isoforms.
Peter Koopman - One of the best experts on this subject based on the ideXlab platform.
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Redd1 is a novel marker of Testis Development but is not required for normal male reproduction.
Sexual development : genetics molecular biology evolution endocrinology embryology and pathology of sex determination and differentiation, 2012Co-Authors: Amanda J. Notini, Peter Koopman, Sonja E. Gustin, Patrick S. Western, Peter J. Mcclive, Vincent R. Harley, Sarah J Meachem, J. A. Van Den Bergen, Andrew H. SinclairAbstract:In an effort to identify novel candidate genes involved in Testis determination, we previously used suppression subtraction hybridisation PCR on male and female whole embryonic (12.0–12.5 days post coitum) mouse gonads. One gene to emerge from our screen was Redd1 . In the current study, we demonstrate by whole-mount in situ hybridisation that Redd1 is differentially expressed in the developing mouse gonad at the time of sex determination, with higher expression in Testis than ovary. Furthermore, Redd1 expression was first detected as Sry expression peaks, immediately prior to morphological sex determination, suggesting a potential role for Redd1 during Testis Development. To determine the functional importance of this gene during Testis Development, we generated Redd1 -deficient mice. Morphologically, Redd1 -deficient mice were indistinguishable from control littermates and showed normal fertility. Our results show that Redd1 alone is not required for Testis Development or fertility
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Testis Development, fertility, and survival in Ethanolamine kinase 2-deficient mice.
Endocrinology, 2008Co-Authors: Sonja E. Gustin, Peter Koopman, Patrick S. Western, Peter J. Mcclive, Vincent R. Harley, Andrew H. SinclairAbstract:Ethanolamine kinase 2 (Eki2) was previously isolated from a differential expression screen designed to identify candidate genes involved in Testis Development and differentiation. In mouse, Eki2 is specifically up-regulated in Sertoli cells of the developing Testis at the time of sex determination. Based on this expression profile, Eki2 was considered a good candidate Testis-determining gene. To investigate a possible role of Eki2 in Testis Development, we have generated a mouse with targeted disruption of the Eki2 gene by using an EGFP replacement strategy. No abnormalities were detected in the Eki2-deficient mice with regard to embryonic and adult Testis morphology, differentiation, function, or fertility. Furthermore, no significant differences were observed in litter sizes, pup mortality rates, or distribution of the sexes among the offspring. Ethanolamine kinases are involved in the biosynthesis of phosphatidylethanolamine, a major membrane phospholipid. Expression analysis indicates that the absence of an apparent phenotype in the Eki2-deficient mice may be due to compensation by Eki2-family members or the activation of an alternative pathway to generate phosphatidylethanolamine. Expression of EGFP in this mouse model enabled the isolation of gonad cell populations, providing a useful resource from which to obtain relatively pure early steroidogenic cells for further studies.
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sox9 regulates prostaglandin d synthase gene transcription in vivo to ensure Testis Development
Journal of Biological Chemistry, 2007Co-Authors: Dagmar Wilhelm, Ryuji Hiramatsu, Hirofumi Mizusaki, Laura Widjaja, Alexander N Combes, Yoshiakira Kanai, Peter KoopmanAbstract:Abstract In mammals, male sex is determined by the Y-chromosomal gene Sry (sex-determining region of Y chromosome). The expression of Sry and subsequently Sox9 (SRY box containing gene 9) in precursors of the supporting cell lineage results in the differentiation of these cells into Sertoli cells. Sertoli cells in turn orchestrate the Development of all other male-specific cell types. To ensure that Sertoli cells differentiate in sufficient numbers to induce normal Testis Development, the early Testis produces prostaglandin D2 (PGD2), which recruits cells of the supporting cell lineage to a Sertoli cell fate. Here we show that the gene encoding prostaglandin D synthase (Pgds), the enzyme that produces PGD2, is expressed in Sertoli cells immediately after the onset of Sox9 expression. Promoter analysis in silico and in vitro identified a paired SOX/SRY binding site. Interestingly, only SOX9, and not SRY, was able to bind as a dimer to this site and transactivate the Pgds promoter. In line with this, a transgenic mouse model showed that Pgds expression is not affected by ectopic Sry expression. Finally, chromatin immunoprecipitation proved that SOX9 but not SRY binds to the Pgds promoter in vivo.
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Osteopontin and related SIBLING glycoprotein genes are expressed by Sertoli cells during mouse Testis Development
Developmental dynamics : an official publication of the American Association of Anatomists, 2005Co-Authors: Megan J. Wilson, Lucy Liaw, Peter KoopmanAbstract:Matrix proteins play important roles in tissue morphogenesis. We have studied the expression of genes encoding the related SIBLING glycoproteins osteopontin (OPN), bone sialoprotein (BSP), and dentin matrix protein (DMP) during the Development of male and female gonads during mouse embryogenesis. Opn mRNA was expressed specifically by Sertoli cells of the developing Testis cords, in the mesonephric tubules of both sexes, and, transiently, in the Müllerian ducts of both sexes, as determined by whole-mount and section in situ hybridization. OPN protein was detected in the cytoplasm of Sertoli cells and luminal cells of the mesonephric tubules, with small amounts associated with the plasma membrane of germ cells. We found no defects in developing testes of Opn-/- mice using a range of cell type-specific markers, suggesting that other SIBLING proteins may function in Testis Development. Dmp and Bsp mRNA was also expressed in the developing Testis cords, supporting the view that all three SIBLING proteins may contribute to Testis differentiation.
Gerd Scherer - One of the best experts on this subject based on the ideXlab platform.
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Sox9 and Sox8 Are Required for Basal Lamina Integrity of Testis Cords and for Suppression of FOXL2 During Embryonic Testis Development in Mice
Biology of reproduction, 2012Co-Authors: Ina Georg, Francisco J Barrionuevo, Thorsten Wiech, Gerd SchererAbstract:The sex-determining gene Sry and its target gene Sox9 initiate the early steps of Testis Development in mammals. Of the related Sox genes Sox8, Sox9, and Sox10, all expressed during Sertoli cell differentiation, only inactivation of Sox9 before the sex determination stage at Embryonic Day 11.5 (E11.5) causes XY sex reversal, while Sox9 inactivation after this stage has no effect on Testis cord differentiation. We have previously shown that both Sox9 and Sox8 are essential for maintaining testicular function in post-E14.0 Sertoli cells. To gain insight into the molecular and cellular processes underlying the abnormal Development of Sox9 and Sox8 mutant testes, we performed a detailed Developmental study of embryonic and neonatal stages. We observe a progressive disruption of the basal lamina surrounding the Testis cords that starts at E17.5 and already at E15.5 reduced expression levels of collagen IV, collagen IXa3 and testatin, structural components of the basal lamina, and the extracellular matrix transcriptional regulator Scleraxis. Lineage tracing reveals that mutant Sertoli cells delaminate from Testis cords and are present as isolated cells between remaining cords. Also, Sox10 expression is strongly reduced in the absence of Sox9 and/or Sox8. Finally, we document increasing expression of the ovarian marker FOXL2 in mutant cords starting at E15.5, indicating progressive transdifferentiation of mutant Sertoli cells. This study shows that Sox9 and Sox8 maintain integrity of the basal lamina to prevent Testis cord disintegration and that both factors actively suppress the ovarian program during early Testis Development.
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Genes promoting and disturbing Testis Development
Histology and histopathology, 2012Co-Authors: Francisco J Barrionuevo, Gerd Scherer, Miguel Burgos, Rafael JiménezAbstract:Mammals have an XX/XY sex chromosomal sex determination system in which males represent the heterogametic sex. The Y-linked gene, SRY, determines sex by inducing the undifferentiated, bipotential gonads to differentiate as testes, which produce androgens and promote in this way the Development of a male phenotype. Thus, in mammals, sex determination can be equated to Testis determination, which involves several important cell processes, including Sertoli cell differentiation, mesonephric cell migration, Testis cord formation, Testis-specific vascularization, and myoid and Leydig cell differentiation. Many genes are currently known to be involved in Testis Development. Some of them, including SF1, WT1, GATA4 and FOG2, are necessary for the formation of the bipotential, undifferentiated gonad but also have important roles in Testis differentiation. Others can be considered Testis-promoting, differentaition and/or maintenance genes: these include SRY, SOX9, FGF9, PTGDS, SOX8, SOX3, NR0B1, PDGFRa, DMRT1, AMH, NGF, NTF3 and NGFR as the most important examples. Finally, there is a smaller group of genes which are involved in ovarian Development and which can cause aberrant Testis Development if mutated, including RSPO1, WNT4, CTNNB1, FST, BMP2 and FOXL2. In this paper, we review our current knowledge on the function, spatio-temporal expression pattern and mutant sexual phenotypes associated with these genes, and discuss the various roles they play in gonad Development.
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SOX E genes: SOX9 and SOX8 in mammalian Testis Development.
The international journal of biochemistry & cell biology, 2009Co-Authors: Francisco J Barrionuevo, Gerd SchererAbstract:The group E SOX proteins consist of SOX8, SOX9 and SOX10. These transcription factors contain, besides a DNA-binding HMG domain and a transactivation domain, a DNA-dependent dimerization domain, unique among SOX proteins. Among these three SOX E proteins, which are all expressed during mammalian Testis Development, SOX9 stands out in importance. It is SOX9 that becomes activated by SRY in pre-Sertoli cells, executing SRY's role as a Testis-determining factor by inducing Sertoli cell and Testis cord differentiation. However, Sox9 is dispensable during subsequent embryonic and postnatal Testis Development, since ablation of Sox9 at embryonic day 14.0, after the sex determination stage, only leads to late-onset sterility at about 5 months. A similar late male sterility phenotype occurs in constitutive Sox8 null mutants. In the combined absence of Sox9 and Sox8, primary male infertility evolves, revealing functional redundancy. Loss of Sox10 has no effect on Testis Development.
R.r. Behringer - One of the best experts on this subject based on the ideXlab platform.
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wt1 negatively regulates β catenin signaling during Testis Development
Development, 2008Co-Authors: H. Chang, Fei Gao, M.m. Taketo, V. Huff, Florian Guillou, R.r. BehringerAbstract:beta-Catenin, as an important effector of the canonical Wnt signaling pathway and as a regulator of cell adhesion, has been demonstrated to be involved in multiple Developmental processes and tumorigenesis. beta-Catenin expression was found mainly on the Sertoli cell membrane starting from embryonic day 15.5 in the developing testes. However, its potential role in Sertoli cells during Testis formation has not been examined. To determine the function of beta-catenin in Sertoli cells during Testis formation, we either deleted beta-catenin or expressed a constitutively active form of beta-catenin in Sertoli cells. We found that deletion caused no detectable abnormalities. However, stabilization caused severe phenotypes, including testicular cord disruption, germ cell depletion and inhibition of Mullerian duct regression. beta-Catenin stabilization caused changes in Sertoli cell identity and misregulation of inter-Sertoli cell contacts. As Wt1 conditional knockout in Sertoli cells causes similar phenotypes to our stabilized beta-catenin mutants, we then investigated the relationship of Wt1 and beta-catenin in Sertoli cells and found Wt1 inhibits beta-catenin signaling in these cells during Testis Development. Wt1 deletion resulted in upregulation of beta-catenin expression in Sertoli cells both in vitro and in vivo. Our study indicates that Sertoli cell expression of beta-catenin is dispensable for Testis Development. However, the suppression of beta-catenin signaling in these cells is essential for proper Testis formation and Wt1 is a negative regulator of beta-catenin signaling during this Developmental process.
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Wt1 negatively regulates beta-catenin signaling during Testis Development
Development (Cambridge England), 2008Co-Authors: H. Chang, Fei Gao, Florian Jean Louis Guillou, M.m. Taketo, V. Huff, R.r. BehringerAbstract:beta-Catenin, as an important effector of the canonical Wnt signaling pathway and as a regulator of cell adhesion, has been demonstrated to be involved in multiple Developmental processes and tumorigenesis. beta-Catenin expression was found mainly on the Sertoli cell membrane starting from embryonic day 15.5 in the developing testes. However, its potential role in Sertoli cells during Testis formation has not been examined. To determine the function of beta-catenin in Sertoli cells during Testis formation, we either deleted beta-catenin or expressed a constitutively active form of beta-catenin in Sertoli cells. We found that deletion caused no detectable abnormalities. However, stabilization caused severe phenotypes, including testicular cord disruption, germ cell depletion and inhibition of Mullerian duct regression. beta-Catenin stabilization caused changes in Sertoli cell identity and misregulation of inter-Sertoli cell contacts. As Wt1 conditional knockout in Sertoli cells causes similar phenotypes to our stabilized beta-catenin mutants, we then investigated the relationship of Wt1 and beta-catenin in Sertoli cells and found Wt1 inhibits beta-catenin signaling in these cells during Testis Development. Wt1 deletion resulted in upregulation of beta-catenin expression in Sertoli cells both in vitro and in vivo. Our study indicates that Sertoli cell expression of beta-catenin is dispensable for Testis Development. However, the suppression of beta-catenin signaling in these cells is essential for proper Testis formation and Wt1 is a negative regulator of beta-catenin signaling during this Developmental process.