The Experts below are selected from a list of 28320 Experts worldwide ranked by ideXlab platform
Martin M Matzuk - One of the best experts on this subject based on the ideXlab platform.
-
Activins and inhibins: novel regulators of thymocyte development.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Paula Licona-limón, Martin M Matzuk, Germán R. Alemán-muench, Jesús Chimal-monroy, Marina Macías-silva, Eduardo A. García-zepeda, Teresa I. Fortoul, Gloria SoldevilaAbstract:Activins and inhibins are members of the transforming growth factor-{beta} superfamily that act on different cell types and regulate a broad range of cellular processes including proliferation, differentiation, and apoptosis. Here, we provide the first evidence that Activins and inhibins regulate specific checkpoints during thymocyte development. We demonstrate that both activin A and inhibin A promote the DN3-DN4 transition in vitro, although they differentially control the transition to the DP stage. Whereas activin A induces the accumulation of a CD8{sup +}CD24{sup hi}TCR{beta}{sup lo} intermediate subpopulation, inhibin A promotes the differentiation of DN4 to DP. In addition, both activin A and inhibin A appear to promote CD8{sup +}SP differentiation. Moreover, inhibin {alpha} null mice have delayed in vitro T cell development, showing both a decrease in the DN-DP transition and reduced thymocyte numbers, further supporting a role for inhibins in the control of developmental signals taking place during T cell differentiation in vivo.
-
Intraovarian Activins Are Required for Female Fertility
Molecular endocrinology (Baltimore Md.), 2007Co-Authors: Stephanie A. Pangas, Carolina J. Jorgez, Mai Tran, Julio E. Agno, Chester W. Brown, T. Rajendra Kumar, Martin M MatzukAbstract:Activins have diverse roles in multiple physiological processes including reproduction. Mutations and loss of heterozygosity at the human activin receptor ACVR1B and ACVR2 loci are observed in pituitary, pancreatic, and colorectal cancers. Functional studies support intraovarian roles for Activins, although clarifying the in vivo roles has remained elusive due to the perinatal death of activin βA knockout mice. To study the roles of Activins in ovarian growth, differentiation, and cancer, a tissue-specific knockout system was designed to ablate ovarian production of Activins. Mice lacking ovarian activin βA were intercrossed to Inhbb homozygous null mice to produce double activin knockouts. Whereas ovarian βA knockout females are subfertile, βB/βA double mutant females are infertile. Strikingly, the activin βA and βB/βA-deficient ovaries contain increased numbers of functional corpora lutea but do not develop ovarian tumors. Microarray analysis of isolated granulosa cells identifies significant changes in...
-
Activins are critical modulators of growth and survival
Molecular Endocrinology, 2003Co-Authors: Chester W. Brown, Dianne E Houstonhawkins, Martin M MatzukAbstract:Activins betaA and betaB (encoded by Inhba and Inhbb genes, respectively) are related members of the TGF-beta superfamily. Previously, we generated mice with an Inhba knock-in allele (InhbaBK) that directs the expression of activin betaB protein in the spatiotemporal pattern of activin betaA. These mice were small and had shortened life spans, both influenced by the dose of the hypomorphic InhbaBK allele. To understand the mechanism(s) underlying these abnormalities, we now examine growth plates, liver, and kidney and analyze IGF-I, GH, and major urinary proteins. Our studies show that Activins modulate the biological effects of IGF-I without substantial effects on GH, and that activin signaling deficiency also has modest effects on hepatic and renal function. To assess the relative influences of activin betaA and activin betaB, we produced mice that express activin betaB from the InhbaBK allele, and not from its endogenous Inhbb locus. InhbaBK/BK, Inhbb-/- mice have failure of eyelid fusion at birth and demonstrate more severe effects on somatic growth and survival than either of the corresponding single homozygous mutants, showing that somatic growth and life span are supported by both Activins betaA and betaB, although activin betaA plays a more substantial role.
-
follistatin is a modulator of gonadal tumor progression and the activin induced wasting syndrome in inhibin deficient mice
Endocrinology, 2000Co-Authors: Sherry C Cipriano, Rajendra T Kumar, Lei Chen, Martin M MatzukAbstract:Inhibins and Activins are dimeric proteins belonging to the transforming growth factor-β superfamily. Follistatin is an activin-binding protein that antagonizes the function of activin via binding to its β-subunits. Previously, we demonstrated that mice deficient in inhibin develop ovarian and testicular sex cord-stromal tumors of granulosa and Sertoli cell origin, with 100% penetrance as early as 4 weeks of age. Overproduction of Activins in the serum directly causes a cachexia-like wasting syndrome that results in lethality of these mice at an early stage after the onset of the tumors. In an independent set of studies, overexpression of mouse follistatin using the mouse metallothionein I promoter in transgenic mice led to gonadal defects and eventual infertility, primarily due to local effects of follistatin in these tissues. Activin has a positive growth effect on gonadal tumor cells in culture and directly causes the cancer cachexia-like syndrome in inhibin-deficient mice via interaction with activin ...
-
activin signaling through activin receptor type ii causes the cachexia like symptoms in inhibin deficient mice
Molecular Endocrinology, 1996Co-Authors: Katherine A Coerver, Jennie P. Mather, Teresa K. Woodruff, Allan Bradley, Milton J Finegold, Martin M MatzukAbstract:Activins and inhibins, members of the transforming growth factor-p superfamily, are involved in diverse physiological and developmental processes. We have previously shown that mice deficient in cY-inhibin develop gonadal sex cord-stromal tumors at an early age. The tumor development is rapidly followed by a wasting syndrome that includes severe weight loss, hepatocellular necrosis around the central vein, and depletion of the parieta1 cells in the glandular stomach. The liver histology in inhibin-deficient mice is similar to the pathological effects of short-term treatment of rats and mice with recombinant activin A. Consistent with these findings, we have shown that the gonadal tumors in the inhibit+deficient mice secrete high levels of Activins. In addition, Northern blot analysis has localized activin receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumor-produced Activins act through ActRll to cause the wasting syndrome in inhibin-deficient mice. To test this hypothesis and determine the significance of elevated levels of activin signaling through ActRll in viva, we generated compound homozygous mutant mice deficient in both cu-inhibin and ActRII. Despite the continued development of gonadal sex cord-stromal tumors and elevated serum levels of activin A and B, the compound homozygous mutant mice suffered no unusual weight loss, and the stomachs and livers of the majority of the mice were histologically normal. These results demonstrate that increased levels of activin signaling through ActRll
Wylie Vale - One of the best experts on this subject based on the ideXlab platform.
-
cell type specific modulation of pituitary cells by activin inhibin and follistatin
Molecular and Cellular Endocrinology, 2012Co-Authors: Louise M. Bilezikjian, Ezra Wiater, Nicholas J Justice, Alissa N Blackler, Wylie ValeAbstract:Activins are multifunctional proteins and members of the TGF-β superfamily. Activins are expressed locally in most tissues and, analogous to the actions of other members of this large family of pleiotropic factors, play prominent roles in the regulation of diverse biological processes in both differentiated and embryonic stem cells. They have an essential role in maintaining tissue homeostasis in the adult and are known to contribute to the developmental programs in the embryo. Activins are further implicated in the growth and metastasis of tumor cells. Through distinct modes of action, inhibins and follistatins function as antagonists of activin and several other TGF-β family members, including a subset of BMPs/GDFs, and modulate cellular responses and the signaling cascades downstream of these ligands. In the pituitary, the activin pathway is known to regulate key aspects of gonadotrope functions and also exert effects on other pituitary cell types. As in other tissues, activin is produced locally by pituitary cells and acts locally by exerting cell-type specific actions on gonadotropes. These local actions of activin on gonadotropes are modulated by the autocrine/paracrine actions of locally secreted follistatin and by the feedback actions of gonadal inhibin. Knowledge about the mechanism of activin, inhibin and follistatin actions is providing information about their importance for pituitary function as well as their contribution to the pathophysiology of pituitary adenomas. The aim of this review is to highlight recent findings and summarize the evidence that supports the important functions of activin, inhibin and follistatin in the pituitary.
-
activin a bone morphogenetic protein bmp chimeras exhibit bmp like activity and antagonize activin and myostatin
Journal of Biological Chemistry, 2008Co-Authors: Radhika V Korupolu, Wylie Vale, Uwe Muenster, Jessica Read, Wolfgang H. FischerAbstract:Activins and bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta family of growth and differentiation factors that induce signaling in target cells by assembling type II and type I receptors at the cell surface. Ligand residues involved in type II binding are located predominantly in the C-terminal region that forms an extended beta-sheet, whereas residues involved in type I binding are located in the alpha-helical and preceding loop central portion of the molecule. To test whether the central residues are sufficient to determine specificity toward type I receptors, activin A/BMP chimeras were constructed in which the central residues (45-79) of activin A were replaced with corresponding residues of BMP2 and BMP7. The chimeras were assessed for activin type II receptor (Act RII) binding, activin-like bioactivity, and BMP-like activity as well as antagonistic properties toward activin A and myostatin. ActA/BMP7 chimera retained Act RII binding affinity comparable with wild type activin A, whereas ActA/BMP2 chimera showed a slightly reduced affinity toward Act RII. Both the chimeras were devoid of significant activin bioactivity in 293T cells in the A3 Lux reporter assay up to concentrations 10-fold higher than the minimal effective activin A concentration (approximately 4 nM). In contrast, these chimeras showed BMP-like activity in a BRE-Luc assay in HepG2 cells as well as induced osteoblast-like phenotype in C2C12 cells expressing alkaline phosphatase. Furthermore, both the chimeras activated Smad1 but not Smad2 in C2C12 cells. Also, both the chimeras antagonized ligands that signal via activin type II receptor, such as activin A and myostatin. These data indicate that activin residues in the central region determine its specificity toward type I receptors. ActA/BMP chimeras can be useful in the study of receptor specificities and modulation of transforming growth factor-beta members, Activins, and BMPs.
-
Pituitary actions of ligands of the TGF-β family: Activins and inhibins
Reproduction, 2006Co-Authors: Louise M. Bilezikjian, Amy L Blount, Cindy Donaldson, Wylie ValeAbstract:: Activins, as members of the transforming growth factor-beta superfamily, control and orchestrate many physiological processes and are vital for the development, growth and functional integrity of most tissues, including the pituitary. Activins produced by pituitary cells work in conjunction with central, peripheral, and other local factors to influence the function of gonadotropes and maintain a normal reproductive axis. Follistatin, also produced by the pituitary, acts as a local buffer to bind activin and modulate its bioactivity. On the other hand, inhibins of gonadal origin provide an endocrine feedback signal to antagonize activin signaling in cells that express the inhibin co-receptor, betaglycan, such as gonadotropes. This review highlights the pituitary roles of activin and the mechanisms through which these actions are modulated by inhibin and follistatin.
-
Activins and inhibins physiological roles signaling mechanisms and regulation
2005Co-Authors: Peter C. Gray, Craig A. Harrison, Ezra Wiater, Louise M. Bilezikjian, Wylie ValeAbstract:Activins and inhibins belong to the transforming growth factor β (TGFβ) superfamily, which also includes the TGF-β (Massague 1998), bone morphogenetic protein (BMP) (Wozney et al. 1988), growth and differentiation (GDF) and nodal-related families (Schier et al. 2000). In human there are now known to be 42 members of the TGF-β superfamily (reviewed in Shi et al. 2003). This review summarizes the physiological roles of Activins and inhibins, focusing on activin actions in the central nervous system (CNS). In addition, we outline the molecular basis for activin signal transduction and regulation, emphasizing recent advances regarding the structural basis for ligand/receptor interactions and the roles of betaglycan and Cripto in attenuating activin signaling.
-
Activins and Inhibins and Their Signaling
Annals of the New York Academy of Sciences, 2004Co-Authors: Wylie Vale, Craig A. Harrison, Ezra Wiater, Peter C. Gray, Louise M. Bilezikjian, Senyon ChoeAbstract:: Activins and inhibins, which were discovered by virtue of their abilities to stimulate or inhibit, respectively, the secretion of FSH, are members of the transforming growth factor-beta (TGFbeta) superfamily and exert a broad range of effects on the diffentiation, proliferation and functions of numerous cell types. Activins interact with two structurally related classes of serine/threonine kinase receptors (type I and type II). Inhibin antagonizes activin by binding to the proteoglycan, betaglycan, and forming a stable complex with and, thereby, sequestering type II activin receptors while excluding type I receptors. If betaglycan is present, inhibin can also antagonize those bone morphogenic proteins (BMPs) whose signaling is dependent upon access to type II activin receptors. Recent insights regarding the structures of ligands, receptors and their signaling complexes are providing the basis for the development of therapeutics capable of modulating fertility and numerous pathophysiologic processes.
Daniel J Bernard - One of the best experts on this subject based on the ideXlab platform.
-
murine fsh production depends on the activin type ii receptors acvr2a and acvr2b
Endocrinology, 2020Co-Authors: Gauthier Schang, Hailey Schultz, Emilie Brule, Luisina Ongaro, Ulrich Boehm, Xiang Zhou, Ying Wang, Daniel J BernardAbstract:: Activins are selective regulators of follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells. In a gonadotrope-like cell line, LβT2, Activins stimulate FSH via the activin type IIA receptor (ACVR2A) and/or bone morphogenetic protein type II receptor (BMPR2). Consistent with these observations, FSH is greatly reduced, though still present, in global Acvr2a knockout mice. In contrast, FSH production is unaltered in gonadotrope-specific Bmpr2 knockout mice. In light of these results, we questioned whether an additional type II receptor might mediate the actions of Activins or related TGFβ ligands in gonadotropes. We focused on the activin type IIB receptor (ACVR2B), even though it does not mediate activin actions in the gonadotrope-like cell line. Using a Cre-lox strategy, we ablated Acvr2a and/or Acvr2b in murine gonadotropes. The resulting conditional knockout (cKO) animals were compared to littermate controls. Acvr2a cKO (cKO-A) females were subfertile (~70% reduced litter size), cKO-A males were hypogonadal, and both sexes showed marked decreases in serum FSH levels compared to controls. Acvr2b cKO (cKO-B) females were subfertile (~20% reduced litter size), cKO-B males had a moderate decrease in testicular weight, but only males showed a significant decrease in serum FSH levels relative to controls. Simultaneous deletion of both Acvr2a and Acvr2b in gonadotropes led to profound hypogonadism and FSH deficiency in both sexes; females were acyclic and sterile. Collectively, these data demonstrate that ACVR2A and ACVR2B are the critical type II receptors through which Activins or related TGFβ ligands induce FSH production in mice in vivo.
-
Activins and Inhibins in Female Reproduction
Encyclopedia of Reproduction, 2018Co-Authors: Daniel J Bernard, Gauthier Schang, Luisina Ongaro, Thomas B. ThompsonAbstract:Inhibins and Activins were discovered as selective regulators of pituitary follicle-stimulating hormone (FSH) secretion. Inhibins are produced in the ovaries and travel via the bloodstream to the anterior pituitary gland where they suppress FSH synthesis. Activins are produced locally in the pituitary and stimulate FSH synthesis. Inhibins and Activins are structurally-related members of the TGFβ superfamily. Inhibins suppress FSH by competitively binding to activin receptors. Inhibins and Activins also play important roles in the ovary where they regulate hormone-dependent and—independent follicle development.
-
Activins regulate 17β hydroxysteroid dehydrogenase type i transcription in murine gonadotrope cells
Journal of Endocrinology, 2009Co-Authors: Beata Bak, Ying Wang, Pankaj Lamba, Laura Carpio, Jinjing L Kipp, Matthew P. Hardy, Kelly E. Mayo, Daniel J BernardAbstract:Activins are pleiotropic members of the TGFb superfamily and were initially characterized based on their abilities to stimulate FSH synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17b-hydroxysteroid dehydrogenase type I (17b-HSD1; Hsd17b1), as an activin- responsive gene in immortalized gonadotrope cells, LbT2. 17b-HSD1 catalyzes the conversion of estrone to the more active 17b-estradiol, and activin A stimulated an increase in this enzymatic activity in these cells. We demonstrated that Activins signaled via the type I receptor, activin receptor-like kinase (ALK4), and the intracellular signaling protein, SMAD2, to regulate Hsd17b1 transcription in immediate- early fashion. Critical cis-elements, including a minimal SMAD-binding element, were mapped to within 100 bp of the start of transcription. Activin/ALK4 signaling also regulated Hsd17b1 transcription in both immortalized and primary cultured murine granulosa cells. The promoter regions mediating basal and activin/ALK4-regulated promoter activity were generally conserved across the different cell types. The data show that activin A rapidly regulates Hsd17b1 transcription in gonadotrope and granulosa cells and may thereby regulate local 17b-estradiol synthesis.
-
A Novel Role for the Forkhead Transcription Factor FOXL2 in Activin A-Regulated Follicle-Stimulating Hormone β Subunit Transcription
Molecular endocrinology (Baltimore Md.), 2009Co-Authors: Pankaj Lamba, Ying Wang, Jérôme Fortin, Stella Tran, Daniel J BernardAbstract:Selective synthesis and release of FSH from pituitary gonadotropes is regulated by Activins. Activins directly stimulate murine FSHβ (Fshb) subunit gene transcription through a consensus 8-bp Sma- and Mad-related protein-binding element (SBE) in the proximal promoter. In contrast, the human FSHB promoter is relatively insensitive to the direct effects of Activins and lacks this SBE. The proximal porcine Fshb promoter, which is highly conserved with human, similarly lacks the 8-bp SBE, but is nonetheless highly sensitive to Activins. We used a comparative approach to determine mechanisms mediating differential activin induction of human, porcine, and murine Fshb/FSHB promoters. We mapped an activin response element in the proximal porcine promoter and identified interspecies variation in a single base pair in close proximity that conferred strong binding of the forkhead transcription factor FOXL2 to the porcine, but not human or murine, promoters. Introduction of the human base pair into the porcine promoter abolished FOXL2 binding and activin A induction. FOXL2 conferred activin A induction to the porcine promoter in heterologous cells, whereas knockdown of the endogenous protein in gonadotropes inhibited the activin A response. The murine Fshb promoter lacks the high-affinity FOXL2-binding site, but its activin induction is FOXL2 sensitive. We identified a more proximal FOXL2-binding element in the murine promoter, which is conserved across species. Mutation of this site attenuated activin A induction of both the porcine and murine promoters. Collectively, the data indicate a novel role for FOXL2 in activin A-regulated Fshb transcription.
-
Activins regulate 17β-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells
The Journal of endocrinology, 2009Co-Authors: Beata Bak, Ying Wang, Pankaj Lamba, Laura Carpio, Jinjing L Kipp, Matthew P. Hardy, Kelly E. Mayo, Daniel J BernardAbstract:Activins are pleiotropic members of the TGFbeta superfamily and were initially characterized based on their abilities to stimulate FSH synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD1; Hsd17b1), as an activin-responsive gene in immortalized gonadotrope cells, LbetaT2. 17beta-HSD1 catalyzes the conversion of estrone to the more active 17beta-estradiol, and activin A stimulated an increase in this enzymatic activity in these cells. We demonstrated that Activins signaled via the type I receptor, activin receptor-like kinase (ALK4), and the intracellular signaling protein, SMAD2, to regulate Hsd17b1 transcription in immediate-early fashion. Critical cis-elements, including a minimal SMAD-binding element, were mapped to within 100 bp of the start of transcription. Activin/ALK4 signaling also regulated Hsd17b1 transcription in both immortalized and primary cultured murine granulosa cells. The promoter regions mediating basal and activin/ALK4-regulated promoter activity were generally conserved across the different cell types. The data show that activin A rapidly regulates Hsd17b1 transcription in gonadotrope and granulosa cells and may thereby regulate local 17beta-estradiol synthesis.
Vicki Rosen - One of the best experts on this subject based on the ideXlab platform.
-
Loss of BMPR2 leads to high bone mass due to increased osteoblast activity
Development, 2015Co-Authors: Jonathan W Lowery, Laura W. Gamer, Giuseppe Intini, Sutada Lotinun, Valerie S. Salazar, Roland Baron, Vicki RosenAbstract:Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFb signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and Activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFb signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and Activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of Activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human
-
Loss of BMPR2 leads to high bone mass due to increased osteoblast activity.
Journal of Cell Science, 2015Co-Authors: Jonathan W Lowery, Laura W. Gamer, Giuseppe Intini, Sutada Lotinun, Valerie S. Salazar, Roland Baron, Vicki RosenAbstract:ABSTRACT Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFβ signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and Activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFβ signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and Activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of Activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human health.
Ying Wang - One of the best experts on this subject based on the ideXlab platform.
-
murine fsh production depends on the activin type ii receptors acvr2a and acvr2b
Endocrinology, 2020Co-Authors: Gauthier Schang, Hailey Schultz, Emilie Brule, Luisina Ongaro, Ulrich Boehm, Xiang Zhou, Ying Wang, Daniel J BernardAbstract:: Activins are selective regulators of follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells. In a gonadotrope-like cell line, LβT2, Activins stimulate FSH via the activin type IIA receptor (ACVR2A) and/or bone morphogenetic protein type II receptor (BMPR2). Consistent with these observations, FSH is greatly reduced, though still present, in global Acvr2a knockout mice. In contrast, FSH production is unaltered in gonadotrope-specific Bmpr2 knockout mice. In light of these results, we questioned whether an additional type II receptor might mediate the actions of Activins or related TGFβ ligands in gonadotropes. We focused on the activin type IIB receptor (ACVR2B), even though it does not mediate activin actions in the gonadotrope-like cell line. Using a Cre-lox strategy, we ablated Acvr2a and/or Acvr2b in murine gonadotropes. The resulting conditional knockout (cKO) animals were compared to littermate controls. Acvr2a cKO (cKO-A) females were subfertile (~70% reduced litter size), cKO-A males were hypogonadal, and both sexes showed marked decreases in serum FSH levels compared to controls. Acvr2b cKO (cKO-B) females were subfertile (~20% reduced litter size), cKO-B males had a moderate decrease in testicular weight, but only males showed a significant decrease in serum FSH levels relative to controls. Simultaneous deletion of both Acvr2a and Acvr2b in gonadotropes led to profound hypogonadism and FSH deficiency in both sexes; females were acyclic and sterile. Collectively, these data demonstrate that ACVR2A and ACVR2B are the critical type II receptors through which Activins or related TGFβ ligands induce FSH production in mice in vivo.
-
Activin A induction of murine and ovine follicle-stimulating hormone β transcription is SMAD-dependent and TAK1 (MAP3K7)/p38 MAPK-independent in gonadotrope-like cells.
Cellular signalling, 2012Co-Authors: Ying WangAbstract:Abstract Activins stimulate follicle-stimulating hormone (FSH) β subunit (Fshb) gene transcription in pituitary gonadotrope cells. Previous studies suggest that Activins signal via homolog of Drosophila mothers against decapentaplegic (SMAD) proteins to stimulate murine or porcine Fshb promoter activity in the gonadotrope-like cell line, LβT2. In contrast, Activins were suggested to regulate the ovine Fshb promoter via a SMAD-independent pathway involving TGFβ associated kinase 1 (TAK1, MAP3K7) and p38 mitogen activated protein kinase (MAPK). Here, we examined roles for TAK1 and p38 in activin A-stimulated murine and ovine Fshb transcription. The TAK1 inhibitor 5Z-7-Oxozeanol (Oxo) significantly impaired fold activin A induction of murine and ovine Fshb promoter-reporters (Fshb-luc) in LβT2 cells, but only at concentrations 50–100 fold greater than its IC50 for TAK1. Moreover, Oxo failed to inhibit activin A induction of endogenous Fshb mRNA levels or fold induction of Fshb-luc activity by a constitutively active form of the activin type I receptor (ALK4). Oxo, at a concentration 5–10 fold greater than its IC50 for TAK1, attenuated TAK1/TAB2 stimulation of a p38-dependent reporter in the same cells. A Map3k7 siRNA impaired TAK1/TAB2-stimulated p38-dependent reporter activity, but failed to antagonize activin A-stimulated Fshb-luc. Though TAK1 was previously suggested to act via p38 to stimulate the ovine Fshb promoter, activin A failed to stimulate p38 phosphorylation in LβT2 cells. In apparent contrast, however, the p38 inhibitors SB203580 and SB202190 concentration-dependently attenuated activin A-induced Fshb-luc activity. Given the lack of p38 activation, we postulated that the inhibitors might non-selectively antagonize ALK4 activity. Indeed, both attenuated activin A-stimulated SMAD2 phosphorylation, consistent with direct antagonism of ALK4 kinase activity. Finally, we observed that RNA-mediated suppression of Smad4, and to a lesser extent Smad3, attenuated activin A induction of both murine and ovine Fshb promoter-reporters. Collectively, these data suggest that activin A signals via SMAD proteins, but not TAK1 or p38, to regulate murine and ovine Fshb transcription in gonadotrope-like cells.
-
Activins regulate 17β hydroxysteroid dehydrogenase type i transcription in murine gonadotrope cells
Journal of Endocrinology, 2009Co-Authors: Beata Bak, Ying Wang, Pankaj Lamba, Laura Carpio, Jinjing L Kipp, Matthew P. Hardy, Kelly E. Mayo, Daniel J BernardAbstract:Activins are pleiotropic members of the TGFb superfamily and were initially characterized based on their abilities to stimulate FSH synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17b-hydroxysteroid dehydrogenase type I (17b-HSD1; Hsd17b1), as an activin- responsive gene in immortalized gonadotrope cells, LbT2. 17b-HSD1 catalyzes the conversion of estrone to the more active 17b-estradiol, and activin A stimulated an increase in this enzymatic activity in these cells. We demonstrated that Activins signaled via the type I receptor, activin receptor-like kinase (ALK4), and the intracellular signaling protein, SMAD2, to regulate Hsd17b1 transcription in immediate- early fashion. Critical cis-elements, including a minimal SMAD-binding element, were mapped to within 100 bp of the start of transcription. Activin/ALK4 signaling also regulated Hsd17b1 transcription in both immortalized and primary cultured murine granulosa cells. The promoter regions mediating basal and activin/ALK4-regulated promoter activity were generally conserved across the different cell types. The data show that activin A rapidly regulates Hsd17b1 transcription in gonadotrope and granulosa cells and may thereby regulate local 17b-estradiol synthesis.
-
A Novel Role for the Forkhead Transcription Factor FOXL2 in Activin A-Regulated Follicle-Stimulating Hormone β Subunit Transcription
Molecular endocrinology (Baltimore Md.), 2009Co-Authors: Pankaj Lamba, Ying Wang, Jérôme Fortin, Stella Tran, Daniel J BernardAbstract:Selective synthesis and release of FSH from pituitary gonadotropes is regulated by Activins. Activins directly stimulate murine FSHβ (Fshb) subunit gene transcription through a consensus 8-bp Sma- and Mad-related protein-binding element (SBE) in the proximal promoter. In contrast, the human FSHB promoter is relatively insensitive to the direct effects of Activins and lacks this SBE. The proximal porcine Fshb promoter, which is highly conserved with human, similarly lacks the 8-bp SBE, but is nonetheless highly sensitive to Activins. We used a comparative approach to determine mechanisms mediating differential activin induction of human, porcine, and murine Fshb/FSHB promoters. We mapped an activin response element in the proximal porcine promoter and identified interspecies variation in a single base pair in close proximity that conferred strong binding of the forkhead transcription factor FOXL2 to the porcine, but not human or murine, promoters. Introduction of the human base pair into the porcine promoter abolished FOXL2 binding and activin A induction. FOXL2 conferred activin A induction to the porcine promoter in heterologous cells, whereas knockdown of the endogenous protein in gonadotropes inhibited the activin A response. The murine Fshb promoter lacks the high-affinity FOXL2-binding site, but its activin induction is FOXL2 sensitive. We identified a more proximal FOXL2-binding element in the murine promoter, which is conserved across species. Mutation of this site attenuated activin A induction of both the porcine and murine promoters. Collectively, the data indicate a novel role for FOXL2 in activin A-regulated Fshb transcription.
-
Activins regulate 17β-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells
The Journal of endocrinology, 2009Co-Authors: Beata Bak, Ying Wang, Pankaj Lamba, Laura Carpio, Jinjing L Kipp, Matthew P. Hardy, Kelly E. Mayo, Daniel J BernardAbstract:Activins are pleiotropic members of the TGFbeta superfamily and were initially characterized based on their abilities to stimulate FSH synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD1; Hsd17b1), as an activin-responsive gene in immortalized gonadotrope cells, LbetaT2. 17beta-HSD1 catalyzes the conversion of estrone to the more active 17beta-estradiol, and activin A stimulated an increase in this enzymatic activity in these cells. We demonstrated that Activins signaled via the type I receptor, activin receptor-like kinase (ALK4), and the intracellular signaling protein, SMAD2, to regulate Hsd17b1 transcription in immediate-early fashion. Critical cis-elements, including a minimal SMAD-binding element, were mapped to within 100 bp of the start of transcription. Activin/ALK4 signaling also regulated Hsd17b1 transcription in both immortalized and primary cultured murine granulosa cells. The promoter regions mediating basal and activin/ALK4-regulated promoter activity were generally conserved across the different cell types. The data show that activin A rapidly regulates Hsd17b1 transcription in gonadotrope and granulosa cells and may thereby regulate local 17beta-estradiol synthesis.
