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Marilyn B. Renfree - One of the best experts on this subject based on the ideXlab platform.
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Hormonal and Molecular Regulation of Phallus Differentiation in a Marsupial Tammar Wallaby.
Genes, 2020Co-Authors: Yu Chen, Marilyn B. RenfreeAbstract:Congenital anomalies in Phalluses caused by endocrine disruptors have gained a great deal of attention due to its annual increasing rate in males. However, the endocrine-driven molecular regulatory mechanism of abnormal Phallus development is complex and remains largely unknown. Here, we review the direct effect of androgen and oestrogen on molecular regulation in Phalluses using the marsupial tammar wallaby, whose Phallus differentiation occurs after birth. We summarize and discuss the molecular mechanisms underlying Phallus differentiation mediated by sonic hedgehog (SHH) at day 50 pp and Phallus elongation mediated by insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3), as well as multiple Phallus-regulating genes expressed after day 50 pp. We also identify hormone-responsive long non-coding RNAs (lncRNAs) that are co-expressed with their neighboring coding genes. We show that the activation of SHH and IGF1, mediated by balanced androgen receptor (AR) and estrogen receptor 1 (ESR1) signalling, initiates a complex regulatory network in males to constrain the timing of Phallus differentiation and to activate the downstream genes that maintain urethral closure and Phallus elongation at later stages.
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Effects of androgen and oestrogen on IGF pathways controlling Phallus growth.
Reproduction, 2019Co-Authors: Yu Chen, Andrew J. Pask, Geoff Shaw, Asao Fujiyama, Yutaka Suzuki, Sumio Sugano, Marilyn B. RenfreeAbstract:The development of the mammalian Phallus involves hormone-dependent mesenchymal-epithelial signalling mechanisms that contribute to urethral closure and regulation of Phallus elongation and growth. In marsupials, most differentiation and growth of the Phallus occurs post-natally, making them amenable to direct hormone treatment. Expression of IGFs, FGFs, EFNB2, MAFB, DLX5 and AP-1 mRNAs in the Phallus at day 50 post-partum (pp) were altered after treatment of tammar wallaby young from day 20 to 40 pp with androgen, oestrogen or after castration at day 25 pp. However, the most interesting changes occurred in the IGF pathway genes. Androgen treatment upregulated IGF1 in female Phalluses and oestrogen treatment upregulated IGF1 in male Phalluses, but it was downregulated by castration. IGFBP3 was higher in female Phalluses and downregulated by androgen. IGF1 expression was higher in all untreated male than in female Phalluses from day 50 to 150 pp, but IGFBP3 had the reverse pattern. At day 90 pp, when urethral closure in males is progressing and male Phallus growth is accelerating. IGF1 and PCNA protein were only detected in the male urorectal septum, suggesting for the first time that closure and elongation may involve IGF1 activation of cell proliferation specifically in male Phalluses. These effects of sex steroids on gene expression and on the IGF1 signalling pathway in particular, suggest that the developing Phallus may be especially susceptible to perturbation by exogenous hormones.
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Androgen and Oestrogen Affect the Expression of Long Non-Coding RNAs During Phallus Development in a Marsupial.
Non-Coding RNA, 2018Co-Authors: Yu Chen, Andrew J. Pask, Geoff Shaw, Asao Fujiyama, Yoko Kuroki, Atsushi Toyoda, Marilyn B. RenfreeAbstract:There is increasing evidence that long non-coding RNAs (lncRNAs) are important for normal reproductive development, yet very few lncRNAs have been identified in Phalluses so far. Unlike eutherians, Phallus development in the marsupial tammar wallaby occurs post-natally, enabling manipulation not possible in eutherians in which differentiation occurs in utero. We treated with sex steroids to determine the effects of androgen and oestrogen on lncRNA expression during Phallus development. Hormonal manipulations altered the coding and non-coding gene expression profile of Phalluses. We identified several predicted co-regulatory lncRNAs that appear to be co-expressed with the hormone-responsive candidate genes regulating urethral closure and Phallus growth, namely IGF1, AR and ESR1. Interestingly, more than 50% of AR-associated coding genes and lncRNAs were also associated with ESR1. In addition, we identified and validated three novel co-regulatory and hormone-responsive lncRNAs: lnc-BMP5, lnc-ZBTB16 and lncRSPO4. Lnc-BMP5 was detected in the urethral epithelium of male Phalluses and was downregulated by oestrogen in males. Lnc-ZBTB16 was downregulated by oestrogen treatment in male Phalluses at day 50 post-partum (pp). LncRSPO4 was downregulated by adiol treatment in female Phalluses but increased in male Phalluses after castration. Thus, the expression pattern and hormone responsiveness of these lncRNAs suggests a physiological role in the development of the Phallus.
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Hormone-responsive genes in the SHH and WNT/β-catenin signaling pathways influence urethral closure and Phallus growth.
Biology of Reproduction, 2018Co-Authors: Yu Chen, Andrew J. Pask, Geoff Shaw, Asao Fujiyama, Yutaka Suzuki, Sumio Sugano, Marilyn B. RenfreeAbstract:Environmental endocrine disruptors (EEDs) that affect androgen or estrogen activity may disrupt gene regulation during Phallus development to cause hypospadias or a masculinized clitoris. We treated developing male tammar wallabies with estrogen and females with androgen from day 20-40 postpartum (pp) during the androgen imprinting window of sensitivity. Estrogen inhibited Phallus elongation but had no effect on urethral closure and did not significantly depress testicular androgen synthesis. Androgen treatment in females did not promote Phallus elongation but initiated urethral closure. Phalluses were collected for transcriptome sequencing at day 50 pp when they first become sexually dimorphic to examine changes in two signaling pathways, sonic hedgehog (SHH) and wingless-type MMTV integration site family (WNT)/β-catenin. SHH mRNA and β-catenin were predominantly expressed in the urethral epithelium in the tammar Phallus, as in eutherian mammals. Estrogen treatment and castration of males induced an upregulation of SHH, while androgen treatment downregulated SHH. These effects appear to be direct since we detected putative estrogen receptor α (ERα) and androgen receptor (AR) binding sites near SHH. WNT5A, like SHH, was downregulated by androgen, while WNT4 was upregulated in female Phalluses after androgen treatment. After estrogen treatment, WIF1 and WNT7A were both downregulated in male Phalluses. After castration, WNT9A was upregulated. These results suggest that SHH and WNT pathways are regulated by both estrogen and androgen to direct the proliferation and elongation of the Phallus during differentiation. Their response to exogenous hormones makes these genes potential targets of EEDs in the etiology of abnormal Phallus development including hypospadias.
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hormone responsive genes in the shh and wnt β catenin signaling pathways influence urethral closure and Phallus growth
Biology of Reproduction, 2018Co-Authors: Yu Chen, Andrew J. Pask, Geoff Shaw, Asao Fujiyama, Yutaka Suzuki, Sumio Sugano, Marilyn B. RenfreeAbstract:Environmental endocrine disruptors (EEDs) that affect androgen or estrogen activity may disrupt gene regulation during Phallus development to cause hypospadias or a masculinized clitoris. We treated developing male tammar wallabies with estrogen and females with androgen from day 20-40 postpartum (pp) during the androgen imprinting window of sensitivity. Estrogen inhibited Phallus elongation but had no effect on urethral closure and did not significantly depress testicular androgen synthesis. Androgen treatment in females did not promote Phallus elongation but initiated urethral closure. Phalluses were collected for transcriptome sequencing at day 50 pp when they first become sexually dimorphic to examine changes in two signaling pathways, sonic hedgehog (SHH) and wingless-type MMTV integration site family (WNT)/β-catenin. SHH mRNA and β-catenin were predominantly expressed in the urethral epithelium in the tammar Phallus, as in eutherian mammals. Estrogen treatment and castration of males induced an upregulation of SHH, while androgen treatment downregulated SHH. These effects appear to be direct since we detected putative estrogen receptor α (ERα) and androgen receptor (AR) binding sites near SHH. WNT5A, like SHH, was downregulated by androgen, while WNT4 was upregulated in female Phalluses after androgen treatment. After estrogen treatment, WIF1 and WNT7A were both downregulated in male Phalluses. After castration, WNT9A was upregulated. These results suggest that SHH and WNT pathways are regulated by both estrogen and androgen to direct the proliferation and elongation of the Phallus during differentiation. Their response to exogenous hormones makes these genes potential targets of EEDs in the etiology of abnormal Phallus development including hypospadias.
Patrice David - One of the best experts on this subject based on the ideXlab platform.
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a Phallus for free quantitative genetics of sexual trade offs in the snail bulinus truncatus
Journal of Evolutionary Biology, 2003Co-Authors: M F Ostrowski, Philippe Jarne, Patrice DavidAbstract:Resource allocation is thought to play a key role in the coexistence of different sexual morphs within hermaphroditic species. Indeed, most models assume that sexual functions are subject to a balance between reproductive advantage and energetic cost. Various types of cost (e.g. organ construction, maintenance and utilization) and levels of trade-off (physiological and genetic) may be considered. We here examine physiological and genetic costs of Phallus construction and maintenance in Bulinus truncatus, a snail species in which aphallic individuals (without Phallus) coexist with regular hermaphrodites. We use a quantitative genetic design involving 37 inbred lines (four populations) known to produce different proportions of aphallics, to test for the existence of genetic and nongenetic correlations between aphally and a range of life-history traits over the totality of the life cycle. Our results show that aphallic and euphallic individuals of the same line do not show consistent differences in either growth, fecundity (including offspring survival), or longevity. Furthermore, none of these traits is genetically correlated across lines with the frequency of the aphallic morph. We conclude that the cost of the construction and maintenance of the Phallus must be very low in this species. Future studies should investigate the cost associated with using the Phallus (i.e. male outcrossing behaviour) to explain the maintenance of high frequencies of aphallic individuals in natural populations.
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A Phallus for free? Quantitative genetics of sexual trade‐offs in the snail Bulinus truncatus
Journal of Evolutionary Biology, 2002Co-Authors: M.‐f. Ostrowski, Philippe Jarne, Patrice DavidAbstract:Resource allocation is thought to play a key role in the coexistence of different sexual morphs within hermaphroditic species. Indeed, most models assume that sexual functions are subject to a balance between reproductive advantage and energetic cost. Various types of cost (e.g. organ construction, maintenance and utilization) and levels of trade-off (physiological and genetic) may be considered. We here examine physiological and genetic costs of Phallus construction and maintenance in Bulinus truncatus, a snail species in which aphallic individuals (without Phallus) coexist with regular hermaphrodites. We use a quantitative genetic design involving 37 inbred lines (four populations) known to produce different proportions of aphallics, to test for the existence of genetic and nongenetic correlations between aphally and a range of life-history traits over the totality of the life cycle. Our results show that aphallic and euphallic individuals of the same line do not show consistent differences in either growth, fecundity (including offspring survival), or longevity. Furthermore, none of these traits is genetically correlated across lines with the frequency of the aphallic morph. We conclude that the cost of the construction and maintenance of the Phallus must be very low in this species. Future studies should investigate the cost associated with using the Phallus (i.e. male outcrossing behaviour) to explain the maintenance of high frequencies of aphallic individuals in natural populations.
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Ontogenetic reaction norm for binary traits: the timing of Phallus development in the snail Bulinus truncatus.
Heredity, 2002Co-Authors: M.‐f. Ostrowski, Philippe Jarne, Berticat O, Patrice DavidAbstract:Ontogenetic reaction norm for binary traits: the timing of Phallus development in the snail Bulinus truncatus
Holzenthal, Ralph W. - One of the best experts on this subject based on the ideXlab platform.
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Figure 15. - Leucotrichiadianeae sp. n. (UMSP000201649). Male genitalia: A segments IX–X, lateral (base of Phallus crosshatched) B segments VII–VIII and segment IX margin, lateral C segments IX–X, dorsal D segments VII–IX, ventral E Phallus, lateral
2018Co-Authors: Thomson, Robin E., Holzenthal, Ralph W.Abstract:Figure 15. - Leucotrichiadianeae sp. n. (UMSP000201649). Male genitalia: A segments IX–X, lateral (base of Phallus crosshatched) B segments VII–VIII and segment IX margin, lateral C segments IX–X, dorsal D segments VII–IX, ventral E Phallus, lateral F Phallus, dorsal
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Figure 35. - Leucotrichiaprocera sp. n. (UMSP000047406). Male genitalia: A segments IX–X, lateral (base of Phallus crosshatched) B segments VII–VIII and segment IX margin, lateral C segments IX–X, dorsal D segments VII–IX, ventral E Phallus, lateral
2018Co-Authors: Thomson, Robin E., Holzenthal, Ralph W.Abstract:Figure 35. - Leucotrichiaprocera sp. n. (UMSP000047406). Male genitalia: A segments IX–X, lateral (base of Phallus crosshatched) B segments VII–VIII and segment IX margin, lateral C segments IX–X, dorsal D segments VII–IX, ventral E Phallus, lateral F Phallus, dorsal
Thomson, Robin E. - One of the best experts on this subject based on the ideXlab platform.
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Figure 15. - Leucotrichiadianeae sp. n. (UMSP000201649). Male genitalia: A segments IX–X, lateral (base of Phallus crosshatched) B segments VII–VIII and segment IX margin, lateral C segments IX–X, dorsal D segments VII–IX, ventral E Phallus, lateral
2018Co-Authors: Thomson, Robin E., Holzenthal, Ralph W.Abstract:Figure 15. - Leucotrichiadianeae sp. n. (UMSP000201649). Male genitalia: A segments IX–X, lateral (base of Phallus crosshatched) B segments VII–VIII and segment IX margin, lateral C segments IX–X, dorsal D segments VII–IX, ventral E Phallus, lateral F Phallus, dorsal
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Figure 35. - Leucotrichiaprocera sp. n. (UMSP000047406). Male genitalia: A segments IX–X, lateral (base of Phallus crosshatched) B segments VII–VIII and segment IX margin, lateral C segments IX–X, dorsal D segments VII–IX, ventral E Phallus, lateral
2018Co-Authors: Thomson, Robin E., Holzenthal, Ralph W.Abstract:Figure 35. - Leucotrichiaprocera sp. n. (UMSP000047406). Male genitalia: A segments IX–X, lateral (base of Phallus crosshatched) B segments VII–VIII and segment IX margin, lateral C segments IX–X, dorsal D segments VII–IX, ventral E Phallus, lateral F Phallus, dorsal
Geoff Shaw - One of the best experts on this subject based on the ideXlab platform.
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Effects of androgen and oestrogen on IGF pathways controlling Phallus growth.
Reproduction, 2019Co-Authors: Yu Chen, Andrew J. Pask, Geoff Shaw, Asao Fujiyama, Yutaka Suzuki, Sumio Sugano, Marilyn B. RenfreeAbstract:The development of the mammalian Phallus involves hormone-dependent mesenchymal-epithelial signalling mechanisms that contribute to urethral closure and regulation of Phallus elongation and growth. In marsupials, most differentiation and growth of the Phallus occurs post-natally, making them amenable to direct hormone treatment. Expression of IGFs, FGFs, EFNB2, MAFB, DLX5 and AP-1 mRNAs in the Phallus at day 50 post-partum (pp) were altered after treatment of tammar wallaby young from day 20 to 40 pp with androgen, oestrogen or after castration at day 25 pp. However, the most interesting changes occurred in the IGF pathway genes. Androgen treatment upregulated IGF1 in female Phalluses and oestrogen treatment upregulated IGF1 in male Phalluses, but it was downregulated by castration. IGFBP3 was higher in female Phalluses and downregulated by androgen. IGF1 expression was higher in all untreated male than in female Phalluses from day 50 to 150 pp, but IGFBP3 had the reverse pattern. At day 90 pp, when urethral closure in males is progressing and male Phallus growth is accelerating. IGF1 and PCNA protein were only detected in the male urorectal septum, suggesting for the first time that closure and elongation may involve IGF1 activation of cell proliferation specifically in male Phalluses. These effects of sex steroids on gene expression and on the IGF1 signalling pathway in particular, suggest that the developing Phallus may be especially susceptible to perturbation by exogenous hormones.
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Androgen and Oestrogen Affect the Expression of Long Non-Coding RNAs During Phallus Development in a Marsupial.
Non-Coding RNA, 2018Co-Authors: Yu Chen, Andrew J. Pask, Geoff Shaw, Asao Fujiyama, Yoko Kuroki, Atsushi Toyoda, Marilyn B. RenfreeAbstract:There is increasing evidence that long non-coding RNAs (lncRNAs) are important for normal reproductive development, yet very few lncRNAs have been identified in Phalluses so far. Unlike eutherians, Phallus development in the marsupial tammar wallaby occurs post-natally, enabling manipulation not possible in eutherians in which differentiation occurs in utero. We treated with sex steroids to determine the effects of androgen and oestrogen on lncRNA expression during Phallus development. Hormonal manipulations altered the coding and non-coding gene expression profile of Phalluses. We identified several predicted co-regulatory lncRNAs that appear to be co-expressed with the hormone-responsive candidate genes regulating urethral closure and Phallus growth, namely IGF1, AR and ESR1. Interestingly, more than 50% of AR-associated coding genes and lncRNAs were also associated with ESR1. In addition, we identified and validated three novel co-regulatory and hormone-responsive lncRNAs: lnc-BMP5, lnc-ZBTB16 and lncRSPO4. Lnc-BMP5 was detected in the urethral epithelium of male Phalluses and was downregulated by oestrogen in males. Lnc-ZBTB16 was downregulated by oestrogen treatment in male Phalluses at day 50 post-partum (pp). LncRSPO4 was downregulated by adiol treatment in female Phalluses but increased in male Phalluses after castration. Thus, the expression pattern and hormone responsiveness of these lncRNAs suggests a physiological role in the development of the Phallus.
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Hormone-responsive genes in the SHH and WNT/β-catenin signaling pathways influence urethral closure and Phallus growth.
Biology of Reproduction, 2018Co-Authors: Yu Chen, Andrew J. Pask, Geoff Shaw, Asao Fujiyama, Yutaka Suzuki, Sumio Sugano, Marilyn B. RenfreeAbstract:Environmental endocrine disruptors (EEDs) that affect androgen or estrogen activity may disrupt gene regulation during Phallus development to cause hypospadias or a masculinized clitoris. We treated developing male tammar wallabies with estrogen and females with androgen from day 20-40 postpartum (pp) during the androgen imprinting window of sensitivity. Estrogen inhibited Phallus elongation but had no effect on urethral closure and did not significantly depress testicular androgen synthesis. Androgen treatment in females did not promote Phallus elongation but initiated urethral closure. Phalluses were collected for transcriptome sequencing at day 50 pp when they first become sexually dimorphic to examine changes in two signaling pathways, sonic hedgehog (SHH) and wingless-type MMTV integration site family (WNT)/β-catenin. SHH mRNA and β-catenin were predominantly expressed in the urethral epithelium in the tammar Phallus, as in eutherian mammals. Estrogen treatment and castration of males induced an upregulation of SHH, while androgen treatment downregulated SHH. These effects appear to be direct since we detected putative estrogen receptor α (ERα) and androgen receptor (AR) binding sites near SHH. WNT5A, like SHH, was downregulated by androgen, while WNT4 was upregulated in female Phalluses after androgen treatment. After estrogen treatment, WIF1 and WNT7A were both downregulated in male Phalluses. After castration, WNT9A was upregulated. These results suggest that SHH and WNT pathways are regulated by both estrogen and androgen to direct the proliferation and elongation of the Phallus during differentiation. Their response to exogenous hormones makes these genes potential targets of EEDs in the etiology of abnormal Phallus development including hypospadias.
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hormone responsive genes in the shh and wnt β catenin signaling pathways influence urethral closure and Phallus growth
Biology of Reproduction, 2018Co-Authors: Yu Chen, Andrew J. Pask, Geoff Shaw, Asao Fujiyama, Yutaka Suzuki, Sumio Sugano, Marilyn B. RenfreeAbstract:Environmental endocrine disruptors (EEDs) that affect androgen or estrogen activity may disrupt gene regulation during Phallus development to cause hypospadias or a masculinized clitoris. We treated developing male tammar wallabies with estrogen and females with androgen from day 20-40 postpartum (pp) during the androgen imprinting window of sensitivity. Estrogen inhibited Phallus elongation but had no effect on urethral closure and did not significantly depress testicular androgen synthesis. Androgen treatment in females did not promote Phallus elongation but initiated urethral closure. Phalluses were collected for transcriptome sequencing at day 50 pp when they first become sexually dimorphic to examine changes in two signaling pathways, sonic hedgehog (SHH) and wingless-type MMTV integration site family (WNT)/β-catenin. SHH mRNA and β-catenin were predominantly expressed in the urethral epithelium in the tammar Phallus, as in eutherian mammals. Estrogen treatment and castration of males induced an upregulation of SHH, while androgen treatment downregulated SHH. These effects appear to be direct since we detected putative estrogen receptor α (ERα) and androgen receptor (AR) binding sites near SHH. WNT5A, like SHH, was downregulated by androgen, while WNT4 was upregulated in female Phalluses after androgen treatment. After estrogen treatment, WIF1 and WNT7A were both downregulated in male Phalluses. After castration, WNT9A was upregulated. These results suggest that SHH and WNT pathways are regulated by both estrogen and androgen to direct the proliferation and elongation of the Phallus during differentiation. Their response to exogenous hormones makes these genes potential targets of EEDs in the etiology of abnormal Phallus development including hypospadias.
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A dual role for SHH during Phallus development in a marsupial.
Sexual Development, 2014Co-Authors: Keng Yih Chew, Andrew J. Pask, Geoff Shaw, Danielle Hickford, Marilyn B. RenfreeAbstract:The mammalian Phallus arises from identical primordia in both sexes and is patterned in part by the key morphogen Sonic hedgehog (SHH). We have investigated SHH and other morphogens during Phallus development in the tammar wallaby. In this marsupial, testis differentiation and androgen production occurs just after birth, but it takes a further 50-60 days before the Phallus becomes sexually dimorphic. One day before birth, SHH was expressed in both sexes in the urethral epithelium. In males, there was a marked upregulation of SHH, GLI2, and AR at day 50 postpartum, a time when testicular androgen production falls. SHH, GLI2, and AR were downregulated in female pouch young treated with androstanediol from days 24-50, but not when treatments were begun at day 29, suggesting an early window of androgen sensitivity. SHH, GLI2, and AR expression in the Phallus of males castrated at day 23 did not differ from controls, but there was an increase in SHH and GLI2 and a decrease in FGF8 and BMP4 expression when the animals were castrated at day 29. These results suggest that the early patterning by SHH is androgen-independent followed by an androgen-dependent window of sensitivity and a sharp rise in SHH expression after androgen withdrawal at day 50.
