Ruey-Sheng Wang - Academia.edu (original) (raw)

Uploads

Papers by Ruey-Sheng Wang

Research paper thumbnail of Androgen Receptor in Sertoli Cell Is Essential for Germ Cell Nursery and Junctional Complex Formation in Mouse Testes

Endocrinology, 2006

To examine the role of androgen receptor (AR) in Sertoli cells (SC), we used a SC-specific AR kno... more To examine the role of androgen receptor (AR) in Sertoli cells (SC), we used a SC-specific AR knockout (S-AR ؊/y ) mouse to further evaluate the chronological changes of seminiferous tubules and the molecular mechanisms of SC androgen/AR signals on spermatogenesis. Testes morphology began changing as early as postnatal day (PD) 10.5 in wild-type (WT), but not in S-AR ؊/y mice. After puberty (PD 50), the SC nuclei of WT testes migrated to the basal area of the seminiferous epithelium; however, in S-AR ؊/y testes, SC nuclei were disarranged and dislocated. Results from electron microscopy further showed an obvious duplication of basal lamina of the seminiferous epithelium in S-AR ؊/y testes at PD 50 compared with WT testes. Using quantitative RT-PCR analyses, the expression of SC gene profiles were compared in PD 10.5 testes. In S-AR ؊/y testes, the expression levels of 1) vimentin were significantly increased and laminin ␣5 was significantly de-creased in PD 10.5, which contributed to functional defects in cytoskeletons and production of the basement membrane component of SC leading to cell morphology deterioration and thus affecting the integrity of seminiferous epithelium; 2) claudin-11, occludin, and gelsolin were significantly decreased in PD 10.5, which contributed to defects in intact junctional complex formation of SC leading to impairment of the integrity of the blood-testis barrier; 3) calcium channel, voltage-dependent, P/Q-type, ␣1A subunit; tissue-type plasminogen activator; transferrin; and epidermal fatty-acidbinding protein were significantly decreased in PD 10.5, which contributed to functional defects in production and/or secretion of specific proteases, transport proteins, and paracrine factors of SC, leading to impairment of its germ cells' nursery functions.

Research paper thumbnail of Testicular Cell-Specific Androgen Receptor Knockout Mice Androgen Receptor Roles in Spermatogenesis and Fertility: Lessons from

Androgens are critical steroid hormones that determine the expression of the male phenotype, incl... more Androgens are critical steroid hormones that determine the expression of the male phenotype, including the outward development of secondary sex characteristics as well as the initiation and maintenance of spermatogenesis. Their actions are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. AR functions as a ligand-dependent transcription factor, regulating expression of an array of androgen-responsive genes. Androgen and the AR play important roles in male spermatogenesis and fertility. The recent generation and characterization of male total and conditional AR knockout mice from different laboratories demonstrated the necessity of AR signaling for both external and internal male phenotype development. As expected, the male total AR knockout mice exhibited female-typical external appearance (including a vagina with a blind end and a clitorislike phallus), the testis was located abdominally, and germ cell development was severely disrupted, which was similar to a human complete androgen insensitivity syndrome or testicular feminization mouse. However, the process of spermatogenesis is highly dependent on autocrine and paracrine communication among testicular cell types, and the disruption of AR throughout an experimental animal cannot answer the question about how AR in each type of testicular cell can play roles in the process of spermatogenesis. In this review, we provide new insights by comparing the results of cell-specific

Research paper thumbnail of Subfertility and defective folliculogenesis in female mice lacking androgen receptor

Proceedings of The National Academy of Sciences, 2004

The roles of the androgen receptor (AR) in female fertility and ovarian function remain largely u... more The roles of the androgen receptor (AR) in female fertility and ovarian function remain largely unknown. Here we report on the generation of female mice lacking AR (AR ؊/؊ ) and the resulting influences on the reproductive system. Female AR ؊/؊ mice appear normal but show longer estrous cycles and reduced fertility. The ovaries from sexually mature AR ؊/؊ females exhibited a marked reduction in the number of corpora lutea. After superovulation treatment, the AR ؊/؊ ovaries produced fewer oocytes and also showed fewer corpora lutea. During the periovulatory period, an intensive granulosa apoptosis event occurs in the AR ؊/؊ preovulatory follicles, concurrent with the down-regulation of p21 and progesterone receptor expression. Furthermore, the defective conformation of the cumulus cell-oocyte complex from the AR ؊/؊ females implies a lower fertilization capability of the AR ؊/؊ oocytes. In addition to insufficient progesterone production, the diminished endometrial growth in uteri in response to exogenous gonadotropins indicates that AR ؊/؊ females exhibit a luteal phase defect. Taken together, these data provide in vivo evidence showing that AR plays an important role in female reproduction.

Research paper thumbnail of Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells

Proceedings of The National Academy of Sciences, 2004

Androgens and the androgen receptor (AR) play important roles in male fertility, although the det... more Androgens and the androgen receptor (AR) play important roles in male fertility, although the detailed mechanisms, particularly how androgen͞AR influences spermatogenesis in particular cell types, remain unclear. Using a Cre-Lox conditional knockout strategy, we generated a tissue-specific knockout mouse with the AR gene deleted only in Sertoli cells (S-AR ؊/y ). Phenotype analyses show the S-AR ؊/y mice were indistinguishable from WT AR mice (B6 AR ؉/y ) with the exception of testes, which were significantly atrophied. S-AR ؊/y mice were infertile, with spermatogenic arrest predominately at the diplotene premeiotic stage and almost no sperm detected in the epididymides. S-AR ؊/y mice also have lower serum testosterone concentrations and higher serum leuteinizing hormone concentrations than B6 AR ؉/y mice. Further mechanistic studies demonstrated that S-AR ؊/y mice have defects in the expression of anti-Mü llerian hormone, androgen-binding protein, cyclin A1, and sperm-1, which play important roles in the control of spermatogenesis and͞or steroidogenesis. Together, our Sertoli cell-specific AR knockout mice provide in vivo evidence of the need for functional AR in Sertoli cells to maintain normal spermatogenesis and testosterone production, and ensure normal male fertility. knockout mice ͉ anti-Mü llerian hormone ͉ testosterone This work was presented in part at the Jensen Symposium of Nuclear Receptors and Endocrine Disorders, December 5-7, 2003, Cincinnati, OH.

Research paper thumbnail of Global analysis of differentially expressed genes in early gestational decidua and chorionic villi using a 9600 human cDNA microarray

Molecular Human Reproduction, 2002

J.J.W.Chen and C.R.Teng contributed equally to this work.

Research paper thumbnail of Androgen Receptor Roles in Spermatogenesis and Fertility: Lessons from Testicular Cell-Specific Androgen Receptor Knockout Mice

Endocrine Reviews, 2009

Androgens are critical steroid hormones that determine the expression of the male phenotype, incl... more Androgens are critical steroid hormones that determine the expression of the male phenotype, including the outward development of secondary sex characteristics as well as the initiation and maintenance of spermatogenesis. Their actions are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. AR functions as a ligand-dependent transcription factor, regulating expression of an array of androgen-responsive genes. Androgen and the AR play important roles in male spermatogenesis and fertility. The recent generation and characterization of male total and conditional AR knockout mice from different laboratories demonstrated the necessity of AR signaling for both external and internal male phenotype development. As expected, the male total AR knockout mice exhibited female-typical external appearance (including a vagina with a blind end and a clitorislike phallus), the testis was located abdominally, and germ cell development was severely disrupted, which was similar to a human complete androgen insensitivity syndrome or testicular feminization mouse. However, the process of spermatogenesis is highly dependent on autocrine and paracrine communication among testicular cell types, and the disruption of AR throughout an experimental animal cannot answer the question about how AR in each type of testicular cell can play roles in the process of spermatogenesis. In this review, we provide new insights by comparing the results of cell-specific

Research paper thumbnail of Abnormal Mammary Gland Development and Growth Retardation in Female Mice and MCF7 Breast Cancer Cells Lacking Androgen Receptor

Phenotype analysis of female mice lacking androgen receptor (AR) deficient ( AR Ϫ / Ϫ ) indicates... more Phenotype analysis of female mice lacking androgen receptor (AR) deficient ( AR Ϫ / Ϫ ) indicates that the development of mammary glands is retarded with reduced ductal branching in the prepubertal stages, and fewer Cap cells in the terminal end buds, as well as decreased lobuloalveolar development in adult females, and fewer milk-producing alveoli in the lactating glands. The defective development of AR Ϫ / Ϫ mammary glands involves the defects of insulin-like growth factor I-insulin-like growth factor I receptor and mitogen-activated protein kinase (MAPK) signals as well as estrogen receptor (ER) activity. Similar growth retardation and defects in growth factor-mediated Ras/Raf/MAPK cascade and ER signaling are also found in AR Ϫ / Ϫ MCF7 breast cancer cells. The restoration assays show that AR NH 2 -terminal/DNA-binding domain, but not the ligand-binding domain, is essential for normal MAPK function in MCF7 cells, and an AR mutant (R608K), found in male breast cancer, is associated with the excessive activation of MAPK. Together, our data provide the first in vivo evidence showing that ARmediated MAPK and ER activation may play important roles for mammary gland development and MCF7 breast cancer cell proliferation.

Research paper thumbnail of Insulin and Leptin Resistance With Hyperleptinemia in Mice Lacking Androgen Receptor

Epidemiological evidence suggests that sex differences exist in type 2 diabetes. Men seem to be m... more Epidemiological evidence suggests that sex differences exist in type 2 diabetes. Men seem to be more susceptible than women to the consequences of obesity and sedentary lifestyle, possibly because of differences in insulin sensitivity and regional body fat deposition. Thus, lacking androgen receptor (AR) in male individuals may promote insulin resistance. To determine whether lacking AR in male individuals contributes to in vivo insulin resistance, an AR knockout model (AR Ϫ/y ) was used to study the correlation between AR and insulin resistance. Progressive reduced insulin sensitivity and impaired glucose tolerance were seen in AR Ϫ/y mice with advancing age. Aging AR Ϫ/y mice displayed accelerated weight gain, hyperinsulinemia, and hyperglycemia, and loss of AR contributes to increased triglyceride content in skeletal muscle and liver. Leptin is higher in serum of AR Ϫ/y mice. Treatment with exogenous leptin fails to stimulate weight loss in AR Ϫ/y mice in advanced age, suggesting leptin resistance in the AR Ϫ/y mice. Exogenous dihydrotestosterone replacement fails to reverse the metabolic abnormalities and insulin resistance in AR Ϫ/y mice. Our in vivo studies demonstrate that androgen-AR plays key roles in the development of insulin and leptin resistance, which may contribute to the development of type 2 diabetes and cardiovascular disease.

Research paper thumbnail of Subfertility with Defective Folliculogenesis in Female Mice Lacking Testicular Orphan Nuclear Receptor 4

Molecular Endocrinology, 2008

Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in ma... more Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in male mice. However, its roles in female fertility and ovarian function remain largely unknown. Here we found female mice lacking TR4 (TR4 ؊/؊ ) displayed subfertility and irregular estrous cycles. TR4 ؊/؊ female mice ovaries were smaller with fewer or no preovulatory follicles and corpora lutea. After superovulation, TR4 ؊/؊ female mice produced fewer oocytes, preovulatory follicles, and corpora lutea. In addition, more intensive granulosa apoptosis was found in TR4 ؊/؊ ovaries. Functional analyses suggest that subfertility in TR4 ؊/؊ female mice can be due to an ovarian defect with impaired folliculogenesis rather than a deficiency in pituitary go-nadotropins. Molecular mechanism dissection of defective folliculogenesis found TR4 might induce LH receptor (LHR) gene expression via direct binding to its 5 promoter. The consequence of reduced LHR expression in TR4 ؊/؊ female mice might then result in reduced gonadal sex hormones via reduced expression of enzymes involved in steroidogenesis. Together, our results showed TR4 might play essential roles in normal folliculogenesis by influencing LHR signals. Modulation of TR4 expression and/or activation via its upstream signals or unidentified ligand(s) might allow us to develop small molecule(s) to control folliculogenesis. (Molecular Endocrinology 22: 858-867, 2008)

Research paper thumbnail of Androgen Receptor in Sertoli Cell Is Essential for Germ Cell Nursery and Junctional Complex Formation in Mouse Testes

Endocrinology, 2006

To examine the role of androgen receptor (AR) in Sertoli cells (SC), we used a SC-specific AR kno... more To examine the role of androgen receptor (AR) in Sertoli cells (SC), we used a SC-specific AR knockout (S-AR ؊/y ) mouse to further evaluate the chronological changes of seminiferous tubules and the molecular mechanisms of SC androgen/AR signals on spermatogenesis. Testes morphology began changing as early as postnatal day (PD) 10.5 in wild-type (WT), but not in S-AR ؊/y mice. After puberty (PD 50), the SC nuclei of WT testes migrated to the basal area of the seminiferous epithelium; however, in S-AR ؊/y testes, SC nuclei were disarranged and dislocated. Results from electron microscopy further showed an obvious duplication of basal lamina of the seminiferous epithelium in S-AR ؊/y testes at PD 50 compared with WT testes. Using quantitative RT-PCR analyses, the expression of SC gene profiles were compared in PD 10.5 testes. In S-AR ؊/y testes, the expression levels of 1) vimentin were significantly increased and laminin ␣5 was significantly de-creased in PD 10.5, which contributed to functional defects in cytoskeletons and production of the basement membrane component of SC leading to cell morphology deterioration and thus affecting the integrity of seminiferous epithelium; 2) claudin-11, occludin, and gelsolin were significantly decreased in PD 10.5, which contributed to defects in intact junctional complex formation of SC leading to impairment of the integrity of the blood-testis barrier; 3) calcium channel, voltage-dependent, P/Q-type, ␣1A subunit; tissue-type plasminogen activator; transferrin; and epidermal fatty-acidbinding protein were significantly decreased in PD 10.5, which contributed to functional defects in production and/or secretion of specific proteases, transport proteins, and paracrine factors of SC, leading to impairment of its germ cells' nursery functions.

Research paper thumbnail of Testicular Cell-Specific Androgen Receptor Knockout Mice Androgen Receptor Roles in Spermatogenesis and Fertility: Lessons from

Androgens are critical steroid hormones that determine the expression of the male phenotype, incl... more Androgens are critical steroid hormones that determine the expression of the male phenotype, including the outward development of secondary sex characteristics as well as the initiation and maintenance of spermatogenesis. Their actions are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. AR functions as a ligand-dependent transcription factor, regulating expression of an array of androgen-responsive genes. Androgen and the AR play important roles in male spermatogenesis and fertility. The recent generation and characterization of male total and conditional AR knockout mice from different laboratories demonstrated the necessity of AR signaling for both external and internal male phenotype development. As expected, the male total AR knockout mice exhibited female-typical external appearance (including a vagina with a blind end and a clitorislike phallus), the testis was located abdominally, and germ cell development was severely disrupted, which was similar to a human complete androgen insensitivity syndrome or testicular feminization mouse. However, the process of spermatogenesis is highly dependent on autocrine and paracrine communication among testicular cell types, and the disruption of AR throughout an experimental animal cannot answer the question about how AR in each type of testicular cell can play roles in the process of spermatogenesis. In this review, we provide new insights by comparing the results of cell-specific

Research paper thumbnail of Subfertility and defective folliculogenesis in female mice lacking androgen receptor

Proceedings of The National Academy of Sciences, 2004

The roles of the androgen receptor (AR) in female fertility and ovarian function remain largely u... more The roles of the androgen receptor (AR) in female fertility and ovarian function remain largely unknown. Here we report on the generation of female mice lacking AR (AR ؊/؊ ) and the resulting influences on the reproductive system. Female AR ؊/؊ mice appear normal but show longer estrous cycles and reduced fertility. The ovaries from sexually mature AR ؊/؊ females exhibited a marked reduction in the number of corpora lutea. After superovulation treatment, the AR ؊/؊ ovaries produced fewer oocytes and also showed fewer corpora lutea. During the periovulatory period, an intensive granulosa apoptosis event occurs in the AR ؊/؊ preovulatory follicles, concurrent with the down-regulation of p21 and progesterone receptor expression. Furthermore, the defective conformation of the cumulus cell-oocyte complex from the AR ؊/؊ females implies a lower fertilization capability of the AR ؊/؊ oocytes. In addition to insufficient progesterone production, the diminished endometrial growth in uteri in response to exogenous gonadotropins indicates that AR ؊/؊ females exhibit a luteal phase defect. Taken together, these data provide in vivo evidence showing that AR plays an important role in female reproduction.

Research paper thumbnail of Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells

Proceedings of The National Academy of Sciences, 2004

Androgens and the androgen receptor (AR) play important roles in male fertility, although the det... more Androgens and the androgen receptor (AR) play important roles in male fertility, although the detailed mechanisms, particularly how androgen͞AR influences spermatogenesis in particular cell types, remain unclear. Using a Cre-Lox conditional knockout strategy, we generated a tissue-specific knockout mouse with the AR gene deleted only in Sertoli cells (S-AR ؊/y ). Phenotype analyses show the S-AR ؊/y mice were indistinguishable from WT AR mice (B6 AR ؉/y ) with the exception of testes, which were significantly atrophied. S-AR ؊/y mice were infertile, with spermatogenic arrest predominately at the diplotene premeiotic stage and almost no sperm detected in the epididymides. S-AR ؊/y mice also have lower serum testosterone concentrations and higher serum leuteinizing hormone concentrations than B6 AR ؉/y mice. Further mechanistic studies demonstrated that S-AR ؊/y mice have defects in the expression of anti-Mü llerian hormone, androgen-binding protein, cyclin A1, and sperm-1, which play important roles in the control of spermatogenesis and͞or steroidogenesis. Together, our Sertoli cell-specific AR knockout mice provide in vivo evidence of the need for functional AR in Sertoli cells to maintain normal spermatogenesis and testosterone production, and ensure normal male fertility. knockout mice ͉ anti-Mü llerian hormone ͉ testosterone This work was presented in part at the Jensen Symposium of Nuclear Receptors and Endocrine Disorders, December 5-7, 2003, Cincinnati, OH.

Research paper thumbnail of Global analysis of differentially expressed genes in early gestational decidua and chorionic villi using a 9600 human cDNA microarray

Molecular Human Reproduction, 2002

J.J.W.Chen and C.R.Teng contributed equally to this work.

Research paper thumbnail of Androgen Receptor Roles in Spermatogenesis and Fertility: Lessons from Testicular Cell-Specific Androgen Receptor Knockout Mice

Endocrine Reviews, 2009

Androgens are critical steroid hormones that determine the expression of the male phenotype, incl... more Androgens are critical steroid hormones that determine the expression of the male phenotype, including the outward development of secondary sex characteristics as well as the initiation and maintenance of spermatogenesis. Their actions are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. AR functions as a ligand-dependent transcription factor, regulating expression of an array of androgen-responsive genes. Androgen and the AR play important roles in male spermatogenesis and fertility. The recent generation and characterization of male total and conditional AR knockout mice from different laboratories demonstrated the necessity of AR signaling for both external and internal male phenotype development. As expected, the male total AR knockout mice exhibited female-typical external appearance (including a vagina with a blind end and a clitorislike phallus), the testis was located abdominally, and germ cell development was severely disrupted, which was similar to a human complete androgen insensitivity syndrome or testicular feminization mouse. However, the process of spermatogenesis is highly dependent on autocrine and paracrine communication among testicular cell types, and the disruption of AR throughout an experimental animal cannot answer the question about how AR in each type of testicular cell can play roles in the process of spermatogenesis. In this review, we provide new insights by comparing the results of cell-specific

Research paper thumbnail of Abnormal Mammary Gland Development and Growth Retardation in Female Mice and MCF7 Breast Cancer Cells Lacking Androgen Receptor

Phenotype analysis of female mice lacking androgen receptor (AR) deficient ( AR Ϫ / Ϫ ) indicates... more Phenotype analysis of female mice lacking androgen receptor (AR) deficient ( AR Ϫ / Ϫ ) indicates that the development of mammary glands is retarded with reduced ductal branching in the prepubertal stages, and fewer Cap cells in the terminal end buds, as well as decreased lobuloalveolar development in adult females, and fewer milk-producing alveoli in the lactating glands. The defective development of AR Ϫ / Ϫ mammary glands involves the defects of insulin-like growth factor I-insulin-like growth factor I receptor and mitogen-activated protein kinase (MAPK) signals as well as estrogen receptor (ER) activity. Similar growth retardation and defects in growth factor-mediated Ras/Raf/MAPK cascade and ER signaling are also found in AR Ϫ / Ϫ MCF7 breast cancer cells. The restoration assays show that AR NH 2 -terminal/DNA-binding domain, but not the ligand-binding domain, is essential for normal MAPK function in MCF7 cells, and an AR mutant (R608K), found in male breast cancer, is associated with the excessive activation of MAPK. Together, our data provide the first in vivo evidence showing that ARmediated MAPK and ER activation may play important roles for mammary gland development and MCF7 breast cancer cell proliferation.

Research paper thumbnail of Insulin and Leptin Resistance With Hyperleptinemia in Mice Lacking Androgen Receptor

Epidemiological evidence suggests that sex differences exist in type 2 diabetes. Men seem to be m... more Epidemiological evidence suggests that sex differences exist in type 2 diabetes. Men seem to be more susceptible than women to the consequences of obesity and sedentary lifestyle, possibly because of differences in insulin sensitivity and regional body fat deposition. Thus, lacking androgen receptor (AR) in male individuals may promote insulin resistance. To determine whether lacking AR in male individuals contributes to in vivo insulin resistance, an AR knockout model (AR Ϫ/y ) was used to study the correlation between AR and insulin resistance. Progressive reduced insulin sensitivity and impaired glucose tolerance were seen in AR Ϫ/y mice with advancing age. Aging AR Ϫ/y mice displayed accelerated weight gain, hyperinsulinemia, and hyperglycemia, and loss of AR contributes to increased triglyceride content in skeletal muscle and liver. Leptin is higher in serum of AR Ϫ/y mice. Treatment with exogenous leptin fails to stimulate weight loss in AR Ϫ/y mice in advanced age, suggesting leptin resistance in the AR Ϫ/y mice. Exogenous dihydrotestosterone replacement fails to reverse the metabolic abnormalities and insulin resistance in AR Ϫ/y mice. Our in vivo studies demonstrate that androgen-AR plays key roles in the development of insulin and leptin resistance, which may contribute to the development of type 2 diabetes and cardiovascular disease.

Research paper thumbnail of Subfertility with Defective Folliculogenesis in Female Mice Lacking Testicular Orphan Nuclear Receptor 4

Molecular Endocrinology, 2008

Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in ma... more Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in male mice. However, its roles in female fertility and ovarian function remain largely unknown. Here we found female mice lacking TR4 (TR4 ؊/؊ ) displayed subfertility and irregular estrous cycles. TR4 ؊/؊ female mice ovaries were smaller with fewer or no preovulatory follicles and corpora lutea. After superovulation, TR4 ؊/؊ female mice produced fewer oocytes, preovulatory follicles, and corpora lutea. In addition, more intensive granulosa apoptosis was found in TR4 ؊/؊ ovaries. Functional analyses suggest that subfertility in TR4 ؊/؊ female mice can be due to an ovarian defect with impaired folliculogenesis rather than a deficiency in pituitary go-nadotropins. Molecular mechanism dissection of defective folliculogenesis found TR4 might induce LH receptor (LHR) gene expression via direct binding to its 5 promoter. The consequence of reduced LHR expression in TR4 ؊/؊ female mice might then result in reduced gonadal sex hormones via reduced expression of enzymes involved in steroidogenesis. Together, our results showed TR4 might play essential roles in normal folliculogenesis by influencing LHR signals. Modulation of TR4 expression and/or activation via its upstream signals or unidentified ligand(s) might allow us to develop small molecule(s) to control folliculogenesis. (Molecular Endocrinology 22: 858-867, 2008)