The Experts below are selected from a list of 1050 Experts worldwide ranked by ideXlab platform
Yoshitaka Nagahama - One of the best experts on this subject based on the ideXlab platform.
-
dmy initiates masculinity by altering gsdf sox9a2 RSPO1 expression in medaka oryzias latipes
Scientific Reports, 2016Co-Authors: Tapas Chakraborty, Linyan Zhou, Yoshitaka Nagahama, Aparna Chaudhari, Taisen IguchiAbstract:Dmy initiates masculinity by altering Gsdf / Sox9a2 / RSPO1 expression in medaka ( Oryzias latipes )
-
Dmy initiates masculinity by altering Gsdf/Sox9a2/RSPO1 expression in medaka (Oryzias latipes)
Scientific Reports, 2016Co-Authors: Tapas Chakraborty, Linyan Zhou, Aparna Chaudhari, Taisen Iguchi, Yoshitaka NagahamaAbstract:Dmy initiates masculinity by altering Gsdf / Sox9a2 / RSPO1 expression in medaka ( Oryzias latipes )
-
RSPO1 activated signalling molecules are sufficient to induce ovarian differentiation in xy medaka oryzias latipes
Scientific Reports, 2016Co-Authors: Linyan Zhou, Tapas Charkraborty, Sipra Mohapatra, Yoshitaka Nagahama, Qian Zhou, Yueguang ZhangAbstract:In contrast to our understanding of testicular differentiation, ovarian differentiation is less well understood in vertebrates. In mammals, R-spondin1 (RSPO1), an activator of Wnt/β-catenin signaling pathway, is located upstream of the female sex determination pathway. However, the functions of RSPO1 in ovarian differentiation remain unclear in non-mammalian species. In order to elucidate the detailed functions of Rspo/Wnt signaling pathway in fish sex determination/differentiation, the ectopic expression of the RSPO1 gene was performed in XY medaka (Oryzias latipes). The results obtained demonstrated that the gain of RSPO1 function induced femininity in XY fish. The overexpression of RSPO1 enhanced Wnt4b and β-catenin transcription, and completely suppressed the expression of male-biased genes (Dmy, Gsdf, Sox9a2 and Dmrt1) as well as testicular differentiation. Gonadal reprograming of RSPO1-over-expressed-XY (RSPO1-OV-XY) fish, induced the production of female-biased genes (Cyp19a1a and Foxl2), estradiol-17β production and further female type secondary sexuality. Moreover, RSPO1-OV-XY females were fertile and produced successive generations. Promoter analyses showed that RSPO1 transcription was directly regulated by DM domain genes (Dmy, the sex-determining gene, and Dmrt1) and remained unresponsive to Foxl2. Taken together, our results strongly suggest that RSPO1 is sufficient to activate ovarian development and plays a decisive role in the ovarian differentiation in medaka.
-
R-spondins are involved in the ovarian differentiation in a teleost, medaka ( Oryzias latipes )
BMC Developmental Biology, 2012Co-Authors: Linyan Zhou, Tapas Charkraborty, Xiangguo Yu, Limin Wu, Sipra Mohapatra, Deshou Wang, Yoshitaka NagahamaAbstract:In mammals, R-spondin (Rspo), an activator of the Wnt/β-catenin signaling pathway, has been shown to be involved in ovarian differentiation. However, the role of the Rspo/Wnt/β-catenin signaling pathway in fish gonads is still unknown. In the present study, full-length cDNAs of RSPO1, 2 and 3 were cloned from the gonads of medaka (Oryzias latipes). The deduced amino acid sequences of mRSPO1-3 were shown to have a similar structural organization. Phylogenetic analysis showed that RSPO1, 2 and 3 were specifically clustered into three distinct clads. Tissue distribution revealed that three Rspo genes were abundantly expressed in the brain and ovary. Real-time PCR analysis around hatching (S33-5dah) demonstrated that three Rspo genes were specifically enhanced in female gonads from S38. In situ hybridization (ISH) analysis demonstrated that three Rspo genes were expressed in the germ cell in ovary, but not in testis. Fluorescence multi-color ISH showed that RSPO1 was expressed in both somatic cells and germ cells at 10dah. Exposure to ethinylestradiol (EE2) in XY individuals for one week dramatically enhanced the expression of three Rspo genes both at 0dah and in adulthood. These results suggest that the Rspo-activating signaling pathway is involved in the ovarian differentiation and maintenance in medaka.
Anne-amandine Chassot - One of the best experts on this subject based on the ideXlab platform.
-
Amplification of R-spondin1 signaling induces granulosa cell fate defects and cancers in mouse adult ovary
Oncogene, 2017Co-Authors: M C De Cian, Anne-amandine Chassot, E Pauper, R Bandiera, V P I Vidal, S Sacco, E P Gregoire, C Panzolini, D Wilhelm, Eric PailhouxAbstract:R-spondin1 is a secreted regulator of WNT signaling, involved in both embryonic development and homeostasis of adult organs. It can have a dual role, acting either as a mitogen or as a tumor suppressor. During ovarian development, RSPO1 is a key factor required for sex determination and differentiation of the follicular cell progenitors, but is downregulated after birth. In human, increased RSPO1 expression is associated with ovarian carcinomas, but it is not clear whether it is a cause or a consequence of the tumorigenic process. To address the role of RSPO1 expression in adult ovaries, we generated an RSPO1 gain-of-function mouse model. Females were hypofertile and exhibited various ovarian defects, ranging from cysts to ovarian tumors. Detailed phenotypical characterization showed anomalies in the ovulation process. Although follicles responded to initial follicle-stimulating hormone stimulation and developed normally until the pre-ovulatory stage, they did not progress any further. Although non-ovulated oocytes degenerated, the surrounding follicular cells did not begin atresia. RSPO1-induced expression not only promotes canonical WNT signaling but also alters granulosa cell fate decisions by maintaining epithelial-like traits in these cells. This prevents follicle cells from undergoing apoptosis, leading to the accumulation of granulosa cell tumors that reactivates the epithelial program from their progenitors. Taken together, our data demonstrate that activation of RSPO1 is sufficient in promoting ovarian tumors and thus supports a direct involvement of this gene in the commencement of ovarian cancers.
-
R-spondin1 regulates muscle progenitor cell fusion through control of antagonist Wnt signaling pathways
bioRxiv, 2016Co-Authors: Floriane Lacour, Anne-amandine Chassot, Marie-christine Chaboissier, Elsa Vezin, Marie-claude Sincennes, Robert Mitchell, Ketan Patel, Michael A. Rudnicki, Florian Bentzinger, Fabien Le GrandAbstract:Tissue regeneration requires the selective activation and repression of specific signaling pathways in stem cells. As such, the Wnt signaling pathways have been shown to control stem cell fate. In many cell types, the R-Spondin (Rspo) family of secreted proteins acts as potent activators of the canonical Wnt/β-catenin pathway. Here, we identify RSPO1 as a mediator of skeletal muscle tissue repair. Firstly we show that RSPO1-null muscles do not display any abnormalities at the basal level. However deletion of RSPO1 results in global alteration of muscle regeneration kinetics following acute injury. We found that muscle stem cells lacking RSPO1 show delayed differentiation. Transcriptome analysis further demonstrated that RSPO1 is required for the activation of Wnt/β-catenin target genes in muscle cells. Furthermore, muscle cells lacking RSPO1 fuse with a higher frequency than normal cells, leading to larger myotubes containing more nuclei both in vitro and in vivo. We found the increase in muscle fusion was dependent on up-regulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that antagonistic control of canonical and non-canonical Wnt signaling pathways by RSPO1 in muscle stem cell progeny is important for restitution of normal muscle architecture during skeletal muscle regeneration.
-
R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation
Reproduction, 2014Co-Authors: Anne-amandine Chassot, Isabelle Gillot, Marie-christine ChaboissierAbstract:Sex differentiation is a unique developmental process. Starting from a bipotential gonad, it gives rise to the ovary and the testis, two highly specialized organs that differ morphologically and physiologically despite sharing common reproductive and endocrine functions. This highlights the specific plasticity of the gonadal precursors and the existence of complex antagonistic genetic regulation. Mammalian sex determination is controlled by paternal transmission of the Y-linked gene, sex-determining region Y (SRY). Using mouse models, it has been shown that the main role of Sry is to activate the expression of the transcription factor Sox9; either one of these two genes is necessary and sufficient to allow testicular development through Sertoli cell differentiation. Thus, defects in SRY/Sry and/or SOX9/Sox9 expression result in male-to-female sex reversal of XY individuals. Molecular mechanisms governing ovarian differentiation remained unknown for a long time, until the discovery of the roles of R-spondin1 (RSPO1) and WNT4. In XX individuals, activation of the β-catenin signaling pathway by the secreted proteins RSPO1 and WNT4 is required to allow granulosa cell differentiation and, in turn, ovarian differentiation. Thus, mutations in RSPO1 result in female-to-male sex reversal of XX patients, and mouse models have allowed the identification of genetic cascades activated by RSPO1 and WNT4 to regulate ovarian development. In this review, we will discuss the respective roles of RSPO1, WNT4, and the β-catenin signaling pathway during ovarian differentiation in mice.
-
Disruption of mitotic arrest precedes precocious differentiation and transdifferentiation of pregranulosa cells in the perinatal Wnt4 mutant ovary.
Developmental Biology, 2013Co-Authors: Danielle M. Maatouk, Anne-amandine Chassot, Marie-christine Chaboissier, Lindsey Mork, Blanche CapelAbstract:Mammalian sex determination is controlled by antagonistic pathways that are initially co-expressed in the bipotential gonad and subsequently become male- or female-specific. In XY gonads, testis development is initiated by upregulation of Sox9 by SRY in pre-Sertoli cells. Disruption of either gene leads to complete male-to-female sex reversal. Ovarian development is dependent on canonical Wnt signaling through Wnt4, RSPO1 and β-catenin. However, only a partial female-to-male sex reversal results from disruption of these ovary-promoting genes. In Wnt4 and RSPO1 mutants, there is evidence of pregranulosa cell-to-Sertoli cell transdifferentiation near birth, following a severe decline in germ cells. It is currently unclear why primary sex reversal does not occur at the sex-determining stage, but instead occurs near birth in these mutants. Here we show that Wnt4-null and RSPO1-null pregranulosa cells transition through a differentiated granulosa cell state prior to transdifferentiating towards a Sertoli cell fate. This transition is preceded by a wave of germ cell death that is closely associated with the disruption of pregranulosa cell quiescence. Our results suggest that maintenance of mitotic arrest in pregranulosa cells may preclude upregulation of Sox9 in cases where female sex-determining genes are disrupted. This may explain the lack of complete sex reversal in such mutants at the sex-determining stage.
-
Testicular Differentiation Occurs in Absence of R-spondin1 and Sox9 in Mouse Sex Reversals
PLOS Genetics, 2012Co-Authors: Rowena Lavery, Anne-amandine Chassot, Elodie P. Gregoire, Andreas Schedl, Dirk G. De Rooij, Eva Pauper, Muriel Klopfenstein, Manuel Mark, Norbert B. Ghyselinck, Marie-christine ChaboissierAbstract:In mammals, male sex determination is governed by SRY-dependent activation of Sox9, whereas female development involves R-spondin1 (RSPO1), an activator of the WNT/beta-catenin signaling pathway. Genetic analyses in mice have demonstrated Sry and Sox9 to be both required and sufficient to induce testicular development. These genes are therefore considered as master regulators of the male pathway. Indeed, female-to-male sex reversal in XX RSPO1 mutant mice correlates with Sox9 expression, suggesting that this transcription factor induces testicular differentiation in pathological conditions. Unexpectedly, here we show that testicular differentiation can occur in XX mutants lacking both RSPO1 and Sox9 (referred to as XX RSPO1KOSox9cKO), indicating that Sry and Sox9 are dispensable to induce female-to-male sex reversal. Molecular analyses show expression of both Sox8 and Sox10, suggesting that activation of Sox genes other than Sox9 can induce male differentiation in RSPO1KOSox9cKO mice. Moreover, since testis development occurs in XY RSPO1KOSox9cKO mice, our data show that RSPO1 is the main effector for male-to-female sex reversal in XY Sox9cKO mice. Thus, RSPO1 is an essential activator of ovarian development not only in normal situations, but also in sex reversal situations. Taken together these data demonstrate that both male and female sex differentiation is induced by distinct, active, genetic pathways. The dogma that considers female differentiation as a default pathway therefore needs to be definitively revised.
Linyan Zhou - One of the best experts on this subject based on the ideXlab platform.
-
R-spondin1 signaling pathway is required for both the ovarian and testicular development in a teleosts, Nile tilapia (Oreochromis niloticus).
General and comparative endocrinology, 2016Co-Authors: Limin Wu, Deshou Wang, Peng Yang, Linyan ZhouAbstract:The furin-domain-containing peptide R-spondin 1 (RSPO1) has recently emerged as an important regulator of ovarian development, upregulating the WNT/β-catenin pathway to oppose testis formation in mammals. However, little information has been reported on the RSPO1 signaling pathway in teleosts. In this study, RSPO1 was isolated from the gonads of the Nile tilapia, Oreochromis niloticus. An in situ hybridization analysis demonstrated that RSPO1 is expressed in the germ cells of the ovary and the testis. An ontogenic analysis demonstrated that RSPO1 expression is upregulated just before meiotic initiation in both the ovary and testis during the early developmental stages of the tilapia. The expression pattern is sexually dimorphic from 20days after hatching, with higher expression in the ovary. The reduction of RSPO1 expression by transcription activator-like (TAL) effector nuclease (TALEN) caused retarded ovarian development, the ectopic expression of male-dominant genes, and increased serum 11-ketotestosterone. Intriguingly, a deficiency of RSPO1 in XY fish caused a delay in spermatogenesis, the inhibition of igf3 and amh expression and a reduction in serum 11-ketotestosterone. Furthermore, incubation with FH535, an inhibitor of the RSPO1/Wnt pathway, decreased β-catenin, while increased cyp11c1 and dmrt1 expression in the in vitro cultured ovaries; decreased cyp11c1, amh and igf3 expression in the in vitro cultured testes. Taken together, our data suggest that the RSPO1 signaling pathway might be involved in both ovarian and testicular development in the tilapia.
-
dmy initiates masculinity by altering gsdf sox9a2 RSPO1 expression in medaka oryzias latipes
Scientific Reports, 2016Co-Authors: Tapas Chakraborty, Linyan Zhou, Yoshitaka Nagahama, Aparna Chaudhari, Taisen IguchiAbstract:Dmy initiates masculinity by altering Gsdf / Sox9a2 / RSPO1 expression in medaka ( Oryzias latipes )
-
Dmy initiates masculinity by altering Gsdf/Sox9a2/RSPO1 expression in medaka (Oryzias latipes)
Scientific Reports, 2016Co-Authors: Tapas Chakraborty, Linyan Zhou, Aparna Chaudhari, Taisen Iguchi, Yoshitaka NagahamaAbstract:Dmy initiates masculinity by altering Gsdf / Sox9a2 / RSPO1 expression in medaka ( Oryzias latipes )
-
RSPO1 activated signalling molecules are sufficient to induce ovarian differentiation in xy medaka oryzias latipes
Scientific Reports, 2016Co-Authors: Linyan Zhou, Tapas Charkraborty, Sipra Mohapatra, Yoshitaka Nagahama, Qian Zhou, Yueguang ZhangAbstract:In contrast to our understanding of testicular differentiation, ovarian differentiation is less well understood in vertebrates. In mammals, R-spondin1 (RSPO1), an activator of Wnt/β-catenin signaling pathway, is located upstream of the female sex determination pathway. However, the functions of RSPO1 in ovarian differentiation remain unclear in non-mammalian species. In order to elucidate the detailed functions of Rspo/Wnt signaling pathway in fish sex determination/differentiation, the ectopic expression of the RSPO1 gene was performed in XY medaka (Oryzias latipes). The results obtained demonstrated that the gain of RSPO1 function induced femininity in XY fish. The overexpression of RSPO1 enhanced Wnt4b and β-catenin transcription, and completely suppressed the expression of male-biased genes (Dmy, Gsdf, Sox9a2 and Dmrt1) as well as testicular differentiation. Gonadal reprograming of RSPO1-over-expressed-XY (RSPO1-OV-XY) fish, induced the production of female-biased genes (Cyp19a1a and Foxl2), estradiol-17β production and further female type secondary sexuality. Moreover, RSPO1-OV-XY females were fertile and produced successive generations. Promoter analyses showed that RSPO1 transcription was directly regulated by DM domain genes (Dmy, the sex-determining gene, and Dmrt1) and remained unresponsive to Foxl2. Taken together, our results strongly suggest that RSPO1 is sufficient to activate ovarian development and plays a decisive role in the ovarian differentiation in medaka.
-
R-spondins are involved in the ovarian differentiation in a teleost, medaka ( Oryzias latipes )
BMC Developmental Biology, 2012Co-Authors: Linyan Zhou, Tapas Charkraborty, Xiangguo Yu, Limin Wu, Sipra Mohapatra, Deshou Wang, Yoshitaka NagahamaAbstract:In mammals, R-spondin (Rspo), an activator of the Wnt/β-catenin signaling pathway, has been shown to be involved in ovarian differentiation. However, the role of the Rspo/Wnt/β-catenin signaling pathway in fish gonads is still unknown. In the present study, full-length cDNAs of RSPO1, 2 and 3 were cloned from the gonads of medaka (Oryzias latipes). The deduced amino acid sequences of mRSPO1-3 were shown to have a similar structural organization. Phylogenetic analysis showed that RSPO1, 2 and 3 were specifically clustered into three distinct clads. Tissue distribution revealed that three Rspo genes were abundantly expressed in the brain and ovary. Real-time PCR analysis around hatching (S33-5dah) demonstrated that three Rspo genes were specifically enhanced in female gonads from S38. In situ hybridization (ISH) analysis demonstrated that three Rspo genes were expressed in the germ cell in ovary, but not in testis. Fluorescence multi-color ISH showed that RSPO1 was expressed in both somatic cells and germ cells at 10dah. Exposure to ethinylestradiol (EE2) in XY individuals for one week dramatically enhanced the expression of three Rspo genes both at 0dah and in adulthood. These results suggest that the Rspo-activating signaling pathway is involved in the ovarian differentiation and maintenance in medaka.
Brant M Weinstein - One of the best experts on this subject based on the ideXlab platform.
-
RSPO1/Wnt signaling promotes angiogenesis via
2020Co-Authors: Aniket V Gore, Matthew R Swift, Brigid D Lo, Mary C Mckinney, Wenling Li, Daniel Castranova, Yohsuke Mukouyama, Andrew E Davis, Brant M WeinsteinAbstract:ठSUMMARY Here, we show that a novel RSPO1-Wnt-Vegfc-Vegfr3 signaling pathway plays an essential role in developmental angiogenesis. A mutation in R-spondin1 (RSPO1), a Wnt signaling regulator, was uncovered during a forward-genetic screen for angiogenesisdeficient mutants in the zebrafish. Embryos lacking RSPO1 or the proposed RSPO1 receptor kremen form primary vessels by vasculogenesis, but are defective in subsequent angiogenesis. Endothelial cell-autonomous inhibition of canonical Wnt signaling also blocks angiogenesis in vivo. The pro-angiogenic effects of RSPO1/Wnt signaling are mediated by Vegfc/Vegfr3(Flt4) signaling. Vegfc expression is dependent on RSPO1 and Wnt, and Vegfc and Vegfr3 are necessary to promote angiogenesis downstream from RSPO1-Wnt. As all of these molecules are expressed by the endothelium during sprouting stages, these results suggest that RSPO1-Wnt-VegfC-Vegfr3 signaling plays a crucial role as an endothelial-autonomous permissive cue for developmental angiogenesis.
-
RSPO1 wnt signaling promotes angiogenesis via vegfc vegfr3
Development, 2011Co-Authors: Aniket V Gore, Matthew R Swift, Brigid D Lo, Mary C Mckinney, Wenling Li, Daniel Castranova, Andrew A Davis, Yohsuke Mukouyama, Brant M WeinsteinAbstract:Here, we show that a novel RSPO1-Wnt-Vegfc-Vegfr3 signaling pathway plays an essential role in developmental angiogenesis. A mutation in R-spondin1 (RSPO1), a Wnt signaling regulator, was uncovered during a forward-genetic screen for angiogenesis-deficient mutants in the zebrafish. Embryos lacking RSPO1 or the proposed RSPO1 receptor kremen form primary vessels by vasculogenesis, but are defective in subsequent angiogenesis. Endothelial cell-autonomous inhibition of canonical Wnt signaling also blocks angiogenesis in vivo. The pro-angiogenic effects of RSPO1/Wnt signaling are mediated by Vegfc/Vegfr3(Flt4) signaling. Vegfc expression is dependent on RSPO1 and Wnt, and Vegfc and Vegfr3 are necessary to promote angiogenesis downstream from RSPO1-Wnt. As all of these molecules are expressed by the endothelium during sprouting stages, these results suggest that RSPO1-Wnt-VegfC-Vegfr3 signaling plays a crucial role as an endothelial-autonomous permissive cue for developmental angiogenesis.
-
RSPO1/Wnt signaling promotes angiogenesis via Vegfc/Vegfr3
Development, 2011Co-Authors: Aniket V Gore, Matthew R Swift, Brigid D Lo, Mary C Mckinney, Wenling Li, Daniel Castranova, Andrew A Davis, Yohsuke Mukouyama, Brant M WeinsteinAbstract:Here, we show that a novel RSPO1-Wnt-Vegfc-Vegfr3 signaling pathway plays an essential role in developmental angiogenesis. A mutation in R-spondin1 (RSPO1), a Wnt signaling regulator, was uncovered during a forward-genetic screen for angiogenesis-deficient mutants in the zebrafish. Embryos lacking RSPO1 or the proposed RSPO1 receptor kremen form primary vessels by vasculogenesis, but are defective in subsequent angiogenesis. Endothelial cell-autonomous inhibition of canonical Wnt signaling also blocks angiogenesis in vivo. The pro-angiogenic effects of RSPO1/Wnt signaling are mediated by Vegfc/Vegfr3(Flt4) signaling. Vegfc expression is dependent on RSPO1 and Wnt, and Vegfc and Vegfr3 are necessary to promote angiogenesis downstream from RSPO1-Wnt. As all of these molecules are expressed by the endothelium during sprouting stages, these results suggest that RSPO1-Wnt-VegfC-Vegfr3 signaling plays a crucial role as an endothelial-autonomous permissive cue for developmental angiogenesis.
-
RSPO1 wnt signaling promotes angiogenesis via
2011Co-Authors: Aniket V Gore, Matthew R Swift, Brigid D Lo, Mary C Mckinney, Wenling Li, Daniel Castranova, Yohsuke Mukouyama, Andrew E Davis, Brant M WeinsteinAbstract:ठSUMMARY Here, we show that a novel RSPO1-Wnt-Vegfc-Vegfr3 signaling pathway plays an essential role in developmental angiogenesis. A mutation in R-spondin1 (RSPO1), a Wnt signaling regulator, was uncovered during a forward-genetic screen for angiogenesisdeficient mutants in the zebrafish. Embryos lacking RSPO1 or the proposed RSPO1 receptor kremen form primary vessels by vasculogenesis, but are defective in subsequent angiogenesis. Endothelial cell-autonomous inhibition of canonical Wnt signaling also blocks angiogenesis in vivo. The pro-angiogenic effects of RSPO1/Wnt signaling are mediated by Vegfc/Vegfr3(Flt4) signaling. Vegfc expression is dependent on RSPO1 and Wnt, and Vegfc and Vegfr3 are necessary to promote angiogenesis downstream from RSPO1-Wnt. As all of these molecules are expressed by the endothelium during sprouting stages, these results suggest that RSPO1-Wnt-VegfC-Vegfr3 signaling plays a crucial role as an endothelial-autonomous permissive cue for developmental angiogenesis.
Marie-christine Chaboissier - One of the best experts on this subject based on the ideXlab platform.
-
R-spondin1 deficiency enhances β-Cell neogenesis in a murine model of diabetes.
Pancreas, 2020Co-Authors: Jasleen K. Chahal, Marie-christine Chaboissier, Victor S.c. Wong, Patricia L. BrubakerAbstract:OBJECTIVE: The cWnt activator, R-spondin1 (RSPO1), regulates β-cell growth, function, and neogenesis, although its role in conditions such as streptozotocin (STZ)-induced diabetes is unknown. We hypothesized that RSPO1 deficiency enhances β-cell neogenesis in STZ-induced diabetes. METHODS: Wild-type (RSPO1) and knockout (RSPO1) mice were injected with STZ (40 mg/kg) for 5 days, followed by analysis of oral glucose and insulin tolerance, and were killed on day 6 (acute; 9-11 mice) or 32 (chronic; 11-16 mice). Immunohistochemistry was performed for β-cell apoptosis, proliferation, neogenesis, and markers of β-cell maturity. RESULTS: There was no difference in oral glucose handling between STZ-induced RSPO1 and RSPO1 mice, although RSPO1 mice demonstrated increased insulin sensitivity. β-cell mass, islet number, and islet size distribution did not differ between STZ-induced RSPO1 and RSPO1 mice, but RSPO1 animals had reduced β-cell apoptosis and increased numbers of insulin-positive ductal cells, indicating β-cell neogenesis. Furthermore, the increased β-cell regeneration observed in the RSPO1 animals was associated with a more differentiated/mature β-cell phenotype as assessed by increased immunopositivity for Nkx6.1, MafA, and GLUT2. CONCLUSIONS: These findings indicate that RSPO1 is a negative regulator of β-cell neogenesis, development, and survival in the face of STZ-induced diabetes, providing a therapeutic target for the enhancement of β-cell mass.
-
Mouse Gonad Development in the Absence of the Pro-Ovary Factor WNT4 and the Pro-Testis Factor SOX9.
Cells, 2020Co-Authors: Furong Tang, Marie-christine Chaboissier, Nainoa Richardson, Audrey Albina, Aitana Perea-gomezAbstract:The transcription factors SRY and SOX9 and RSPO1/WNT4/β-Catenin signaling act as antagonistic pathways to drive testis and ovary development respectively, from a common gonadal primordium in mouse embryos. In this work, we took advantage of a double knockout mouse model to study gonadal development when Sox9 and Wnt4 are both mutated. We show that the XX gonad mutant for Wnt4 or for both Wnt4 and Sox9 develop as ovotestes, demonstrating that ectopic SOX9 function is not required for the partial female-to-male sex reversal caused by a Wnt4 mutation. Sox9 deletion in XY gonads leads to ovarian development accompanied by ectopic WNT/β-catenin signaling. In XY Sox9 mutant gonads, SRY-positive supporting precursors adopt a female-like identity and develop as pre-granulosa-like cells. This phenotype cannot be fully prevented by the deletion of Wnt4 or RSPO1, indicating that SOX9 is required for the early determination of the male supporting cell identity independently of repressing RSPO1/WNT4/β-Catenin signaling. However, in XY Sox9 Wnt4 double mutant gonads, pre-granulosa cells are not maintained, as they prematurely differentiate as mature granulosa cells and then trans-differentiate into Sertoli-like cells. Together, our results reveal the dynamics of the specific and independent actions of SOX9 and WNT4 during gonadal differentiation: SOX9 is essential in the testis for early specification of male-supporting cells whereas WNT4 functions in the ovary to maintain female-supporting cell identity and inhibit male-specific vascular and steroidogenic cell differentiation.
-
Sox8 and Sox9 act redundantly for ovarian-to-testicular fate reprogramming in the absence of RSPO1 in mouse sex reversal
bioRxiv, 2019Co-Authors: Marie-christine Chaboissier, Elodie P. Gregoire, Dirk G. De Rooij, Nainoa Richardson, Isabelle Gillot, Sameh A Youssef, Alain De Bruin, Marie-cécile De CianAbstract:In mammals, testicular differentiation is initiated by transcription factors SRY and SOX9 in XY gonads, and ovarian differentiation involves R-spondin1 (RSPO1) mediated activation of WNT/β-catenin signaling in XX gonads. Accordingly, the absence of RSPO1/RSPO1 in XX humans and mice leads to testicular differentiation and female-to-male sex reversal in a manner that does not require Sry or Sox9 in mice. Here we show that an alternate testis-differentiating factor exists and that this factor is Sox8. Specifically, genetic ablation of Sox8 and Sox9 prevents ovarian-to testicular reprogramming observed in XX RSPO1 loss-of-function mice. Consequently, RSPO1 Sox8 Sox9 triple mutant gonads developed as atrophied ovaries. Thus, SOX8 alone can compensate for the loss of SOX9 for Sertoli cell differentiation during female-to-male sex reversal.
-
R-spondin1 Controls Muscle Cell Fusion through Dual Regulation of Antagonistic Wnt Signaling Pathways
Cell Reports, 2017Co-Authors: Floriane Lacour, Elsa Vezin, C. Florian Bentzinger, Marie-claude Sincennes, Lorenzo Giordani, Arnaud Ferry, Robert Mitchell, Ketan Patel, Michael A. Rudnicki, Marie-christine ChaboissierAbstract:Wnt-mediated signals are involved in many important steps in mammalian regeneration. In multiple cell types, the R-spondin (Rspo) family of secreted proteins potently activates the canonical Wnt/β-catenin pathway. Here, we identify RSPO1 as a mediator of skeletal muscle tissue repair. First, we show that deletion of RSPO1 results in global alteration of muscle regeneration kinetics following acute injury. We find that muscle progenitor cells lacking RSPO1 show delayed differentiation due to reduced activation of Wnt/β-catenin target genes. Furthermore, muscle cells lacking RSPO1 have a fusion phenotype leading to larger myotubes containing supernumerary nuclei both in vitro and in vivo. The increase in muscle fusion was dependent on downregulation of Wnt/β-catenin and upregulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that reciprocal control of antagonistic Wnt signaling pathways by RSPO1 in muscle stem cell progeny is a key step ensuring normal tissue architecture restoration following acute damage.
-
R-spondin1 regulates muscle progenitor cell fusion through control of antagonist Wnt signaling pathways
bioRxiv, 2016Co-Authors: Floriane Lacour, Anne-amandine Chassot, Marie-christine Chaboissier, Elsa Vezin, Marie-claude Sincennes, Robert Mitchell, Ketan Patel, Michael A. Rudnicki, Florian Bentzinger, Fabien Le GrandAbstract:Tissue regeneration requires the selective activation and repression of specific signaling pathways in stem cells. As such, the Wnt signaling pathways have been shown to control stem cell fate. In many cell types, the R-Spondin (Rspo) family of secreted proteins acts as potent activators of the canonical Wnt/β-catenin pathway. Here, we identify RSPO1 as a mediator of skeletal muscle tissue repair. Firstly we show that RSPO1-null muscles do not display any abnormalities at the basal level. However deletion of RSPO1 results in global alteration of muscle regeneration kinetics following acute injury. We found that muscle stem cells lacking RSPO1 show delayed differentiation. Transcriptome analysis further demonstrated that RSPO1 is required for the activation of Wnt/β-catenin target genes in muscle cells. Furthermore, muscle cells lacking RSPO1 fuse with a higher frequency than normal cells, leading to larger myotubes containing more nuclei both in vitro and in vivo. We found the increase in muscle fusion was dependent on up-regulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that antagonistic control of canonical and non-canonical Wnt signaling pathways by RSPO1 in muscle stem cell progeny is important for restitution of normal muscle architecture during skeletal muscle regeneration.
