The Experts below are selected from a list of 2583 Experts worldwide ranked by ideXlab platform
Eileen M Shore - One of the best experts on this subject based on the ideXlab platform.
-
granting immunity to fop and catching heterotopic ossification in the act
Seminars in Cell & Developmental Biology, 2016Co-Authors: Frederick S. Kaplan, Robert J. Pignolo, Eileen M ShoreAbstract:The progressive transformation of one organ system into another is a fundamental signature of fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of extraskeletal bone formation in humans. In all affected individuals, FOP is caused by heterozygous missense gain-of-function mutations in Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor. Loss of autoinhibition of the mutant receptor (mACVR1) results in dysregulated BMP pathway signaling, and is necessary for the myriad developmental features of FOP, but does not appear sufficient to induce the episodic flare-ups that lead to disabling post-natal heterotopic endochondral ossification (HEO) and that are a hallmark of the disease. Post-natal FOP flare-ups strongly implicate an underlying immunological trigger involving inflammation and the innate immune system. Recent studies implicate canonical and non-canonical TGFβ/BMP family ligands in the amplification of mACVR1 signaling leading to the formation of FOP lesions and resultant HEO. BMP and Activin ligands that stimulate mACVR1 signaling also have critical regulatory functions in the immune system. Cross-talk between the morphogenetic and immunological pathways that regulate tissue maintenance and wound healing identifies potential robust therapeutic targets for FOP. Here we review current evidence for an immunological trigger for flare-ups and HEO in FOP, propose a working schema for the pathophysiology of observed phenomena, and highlight outstanding questions under investigation.
-
fibrodysplasia ossificans progressiva diagnosis management and therapeutic horizons
Pediatric endocrinology reviews, 2013Co-Authors: Robert J. Pignolo, Eileen M Shore, Frederick S. KaplanAbstract:Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO) which is the most catastrophic of HEO disorders in humans. Flare-ups of FOP are episodic; immobility is cumulative. Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVRI/ ALK2), a bone morphogenetic protein (BMP) type I receptor, exist in all sporadic and familial cases of FOP. The discovery of the FOP gene established a critical milestone in our understanding of FOP, and revealed a highly conserved therapeutic target in the BMP signaling pathway. This discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment of FOP will likely be based on interventions that modulate overactive ACVR1/ALK2 signaling, or that specifically block postnatal HEO, current management is focused on early diagnosis, assiduous avoidance of injury or iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function.
-
fibrodysplasia ossificans progressiva a human genetic disorder of extraskeletal bone formation or how does one tissue become another
Wiley Interdisciplinary Reviews-Developmental Biology, 2012Co-Authors: Eileen M ShoreAbstract:Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disease in which de novo osteogenesis—a developmental process occurring during embryonic skeletal formation—is induced aberrantly and progressively beginning during early childhood in soft connective tissues. Episodic initiation of spontaneous bone-forming lesions occurs over time, affecting a generally predictable sequence of body locations following a pattern similar to that of the developing embryonic skeleton. The heterotopic (extraskeletal) bone formation in FOP can also be induced by connective tissue injury. At the tissue level, an initial tissue degradation phase is followed by a tissue formation phase during which soft connective tissues are replaced by bone tissue through endochondral osteogenesis. This extraskeletal bone is physiologically normal and develops through the same series of tissue differentiation events that occur during normal embryonic skeletal development. The underlying genetic mutation in FOP alters the signals that regulate induction of cell differentiation leading to bone formation. In addition to postnatal heterotopic ossification, FOP patients show specific malformations of skeletal elements indicating effects on bone formation during embryonic development as well. Nearly all cases of FOP are caused by the identical mutation in the ACVR1 gene that causes a single amino acid substitution, R206H, in the bone morphogenetic protein (BMP) type I receptor ACVR1 (formerly known as ALK2). This mutation causes mild constitutive activation of the BMP signaling pathway and identifies ACVR1 as a key regulator of cell fate decisions and bone formation, providing opportunities to investigate previously unrecognized functions for this receptor during tissue development and homeostasis. WIREs Dev Biol 2012, 1:153–165. doi: 10.1002/wdev.9 For further resources related to this article, please visit the WIREs website.
-
the fibrodysplasia ossificans progressiva r206h ACVR1 mutation activates bmp independent chondrogenesis and zebrafish embryo ventralization
Journal of Clinical Investigation, 2009Co-Authors: Qi Shen, Julia Haupt, Frederick S. Kaplan, Takenobu Katagiri, Mary C. Mullins, Petra Seemann, Shawn C Little, Cindy Ast, Stefa N Mundlos, Eileen M ShoreAbstract:Patients with classic fibrodysplasia ossificans progressiva, a disorder characterized by extensive extraskeletal endochondral bone formation, share a recurrent mutation (R206H) within the glycine/serine-rich domain of ACVR1/ALK2, a bone morphogenetic protein type I receptor. Through a series of in vitro assays using several mammalian cell lines and chick limb bud micromass cultures, we determined that mutant R206H ACVR1 activated BMP signaling in the absence of BMP ligand and mediated BMP-independent chondrogenesis that was enhanced by BMP. We further investigated the interaction of mutant R206H ACVR1 with FKBP1A, a glycine/serine domain-binding protein that prevents leaky BMP type I receptor activation in the absence of ligand. The mutant protein exhibited reduced binding to FKBP1A in COS-7 simian kidney cell line assays, suggesting that increased BMP pathway activity in COS-7 cells with R206H ACVR1 is due, at least in part, to decreased binding of this inhibitory factor. Consistent with these findings, in vivo analyses of zebrafish embryos showed BMP-independent hyperactivation of BMP signaling in response to the R206H mutant, resulting in increased embryonic ventralization. These data support the conclusion that the mutant R206H ACVR1 receptor in FOP patients is an activating mutation that induces BMP signaling in a BMP-independent and BMP-responsive manner to promote chondrogenesis, consistent with the ectopic endochondral bone formation in these patients.
-
a recurrent mutation in the bmp type i receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva
Nature Genetics, 2006Co-Authors: Eileen M Shore, Meiqi Xu, George J Feldman, David A Fenstermacher, Michael J Connor, Patricia Delai, David L Glaser, Martine Lemerrer, In Ho Choi, Rolf MorhartAbstract:Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G→A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.
Vesa Kaartinen - One of the best experts on this subject based on the ideXlab platform.
-
activin a receptor type 1 mediated bmp signaling regulates rankl induced osteoclastogenesis via canonical smad signaling pathway
Journal of Biological Chemistry, 2019Co-Authors: Vesa Kaartinen, Yuji MishinaAbstract:Bone morphogenetic proteins (BMPs) are important mediators of osteoclast differentiation. Although accumulating evidence has implicated BMPs in osteoblastogenesis, the mechanisms by which BMPs regulate osteoclastogenesis remain unclear. Activin A receptor type 1 (ACVR1) is a BMP type 1 receptor essential for skeletal development. Here, we observed that BMP-7, which preferentially binds to ACVR1, promotes osteoclast differentiation, suggesting ACVR1 is involved in osteoclastogenesis. To investigate this further, we isolated osteoclasts from either ACVR1-floxed mice or mice with constitutively-activated ACVR1 (caACVR1) carrying tamoxifen-inducible Cre driven by a ubiquitin promotor and induced Cre activity in culture. Osteoclasts from the ACVR1-floxed mice had reduced osteoclast numbers and demineralization activity, whereas those from the caACVR1-mutant mice formed large osteoclasts and demineralized pits, suggesting that BMP signaling through ACVR1 regulates osteoclast fusion and activity. It is reported that BMP-2 binds to BMPR1A, another BMP type 1 receptor, whereas BMP-7 binds to ACVR1 to activate SMAD1/5/9 signaling. Here, Bmpr1a-disrupted osteoclasts displayed reduced phospho-SMAD1/5/9 (pSMAD1/5/9) levels when induced by BMP-2, whereas no impacts on pSMAD1/5/9 were observed when induced by BMP-7. In contract, ACVR1-disrupted osteoclasts displayed reduced pSMAD1/5/9 levels when induced either by BMP-2 or BMP-7, suggesting that ACVR1 is the major receptor for transducing BMP-7 signals in osteoclasts. Indeed, LDN-193189 and LDN-212854, which specifically block SMAD1/5/9 phosphorylation, inhibited osteoclastogenesis of caACVR1-mutant cells. Moreover, increased BMP signaling promoted nuclear translocation of nuclear factor-activated T-cells 1 (NFATc1), which was inhibited by LDN treatments. Taken together, ACVR1-mediated BMP-SMAD signaling activates NFATc1, a regulatory protein crucial for receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis.
-
BmpR1A is a major type 1 BMP receptor for BMP-Smad signaling during skull development
Developmental biology, 2017Co-Authors: Haichun Pan, Vesa Kaartinen, Karen M Lyons, Honghao Zhang, Ponnu Abraham, Yuji MishinaAbstract:Craniosynostosis is caused by premature fusion of one or more sutures in an infant skull, resulting in abnormal facial features. The molecular and cellular mechanisms by which genetic mutations cause craniosynostosis are incompletely characterized, and many of the causative genes for diverse types of syndromic craniosynostosis have not yet been identified. We previously demonstrated that augmentation of BMP signaling mediated by a constitutively active BMP type IA receptor (ca-BmpR1A) in neural crest cells (ca1A hereafter) causes craniosynostosis and superimposition of heterozygous null mutation of Bmpr1a rescues premature suture fusion (ca1A;1aH hereafter). In this study, we superimposed heterozygous null mutations of the other two BMP type I receptors, Bmpr1b and ACVR1 (ca1A;1bH and ca1A;AcH respectively hereafter) to further dissect involvement of BMP-Smad signaling. Unlike caA1;1aH, ca1A;1bH and ca1A;AcH did not restore the craniosynostosis phenotypes. In our in vivo study, Smad-dependent BMP signaling was decreased to normal levels in mut;1aH mice. However, BMP receptor-regulated Smads (R-Smads; pSmad1/5/9 hereafter) levels were comparable between ca1A, ca1A;1bH and ca1A;AcH mice, and elevated compared to control mice. Bmpr1a, Bmpr1b and ACVR1 null cells were used to examine potential mechanisms underlying the differences in ability of heterozygosity for Bmpr1a vs. Bmpr1b or ACVR1 to rescue the mut phenotype. pSmad1/5/9 level was undetectable in Bmpr1a homozygous null cells while pSmad1/5/9 levels did not decrease in Bmpr1b or ACVR1 homozygous null cells. Taken together, our study indicates that different levels of expression and subsequent activation of Smad signaling differentially contribute each BMP type I receptor to BMP-Smad signaling and craniofacial development. These results also suggest differential involvement of each type 1 receptor in pathogenesis of syndromic craniosynostoses.
-
normal gonadotropin production and fertility in gonadotrope specific bmpr1a knockout mice
Journal of Endocrinology, 2016Co-Authors: Xiang Zhou, Vesa Kaartinen, Yuji Mishina, Ying Y Wang, Luisina Ongaro, Ulrich Boehm, Daniel J BernardAbstract:Pituitary follicle-stimulating hormone (FSH) synthesis is regulated by transforming growth factorβsuperfamily ligands, most notably the activins and inhibins. Bone morphogenetic proteins (BMPs) also regulate FSHβ subunit (Fshb) expression in immortalized murine gonadotrope-like LβT2 cells and in primary murine or ovine primary pituitary cultures. BMP2 signals preferentially via the BMP type I receptor, BMPR1A, to stimulate murine Fshb transcription in vitro Here, we used a Cre-lox approach to assess BMPR1A's role in FSH synthesis in mice in vivo Gonadotrope-specific Bmpr1a knockout animals developed normally and had reproductive organ weights comparable with those of controls. Knockouts were fertile, with normal serum gonadotropins and pituitary gonadotropin subunit mRNA expression. Cre-mediated recombination of the floxed Bmpr1a allele was efficient and specific, as indicated by PCR analysis of diverse tissues and isolated gonadotrope cells. Furthermore, BMP2 stimulation of inhibitor of DNA binding 3 expression was impaired in gonadotropes isolated from Bmpr1a knockout mice, confirming the loss of functional receptor protein in these cells. Treatment of purified gonadotropes with small-molecule inhibitors of BMPR1A (and the related receptors BMPR1B and ACVR1) suppressed Fshb mRNA expression, suggesting that an autocrine BMP-like molecule might regulate FSH synthesis. However, deletion of Bmpr1a and ACVR1 in cultured pituitary cells did not alter Fshb expression, indicating that the inhibitors had off-target effects. In sum, BMPs or related ligands acting via BMPR1A or ACVR1 are unlikely to play direct physiological roles in FSH synthesis by murine gonadotrope cells.
-
bmp signaling mediated by constitutively active activin type 1 receptor ACVR1 results in ectopic bone formation localized to distal extremity joints
Developmental Biology, 2015Co-Authors: Shailesh Agarwal, Vesa Kaartinen, Shawn Loder, Cameron Brownley, Oluwatobi Eboda, Jonathan R Peterson, Satoru Hayano, Bingrou Wu, Bin Zhao, Victor C WongAbstract:BMP signaling mediated by ACVR1 plays a critical role for development of multiple structures including the cardiovascular and skeletal systems. While deficient ACVR1 signaling impairs normal embryonic development, hyperactive ACVR1 function (R206H in humans and Q207D mutation in mice, ca-ACVR1) results in formation of heterotopic ossification (HO). We developed a mouse line, which conditionally expresses ca-ACVR1 with Nfatc1-Cre+ transgene. Mutant mice developed ectopic cartilage and bone at the distal joints of the extremities including the interphalangeal joints and hind limb ankles as early as P4 in the absence of trauma or exogenous bone morphogenetic protein (BMP) administration. Micro-CT showed that even at later time points (up to P40), cartilage and bone development persisted at the affected joints most prominently in the ankle. Interestingly, this phenotype was not present in areas of bone outside of the joints – tibia are normal in mutants and littermate controls away from the ankle. These findings demonstrate that this model may allow for further studies of heterotopic ossification, which does not require the use of stem cells, direct trauma or activation with exogenous Cre gene administration.
-
ACVR1 mediated bmp signaling in second heart field is required for arterial pole development implications for myocardial differentiation and regional identity
Developmental Biology, 2014Co-Authors: Penny S Thomas, Jamie Lane, Sudha Rajderkar, Yuji Mishina, Vesa KaartinenAbstract:BMP signaling plays an essential role in second heart field-derived heart and arterial trunk development, including myocardial differentiation, right ventricular growth, and interventricular, outflow tract and aortico-pulmonary septation. It is mediated by a number of different BMP ligands, and receptors, many of which are present simultaneously. The mechanisms by which they regulate morphogenetic events and degree of redundancy amongst them have still to be elucidated. We therefore assessed the role of BMP Type I receptor ACVR1 in anterior second heart field-derived cell development, and compared it with that of BmpR1a. By removing ACVR1 using the driver Mef2c[AHF]-Cre, we show that ACVR1 plays an essential role in arterial pole morphogenesis, identifying defects in outflow tract wall and cushion morphology that preceded a spectrum of septation defects from double outlet right ventricle to common arterial trunk in mutants. Its absence caused dysregulation in gene expression important for myocardial differentiation (Isl1, Fgf8) and regional identity (Tbx2, Tbx3, Tbx20, Tgfb2). Although these defects resemble to some degree those in the equivalent Bmpr1a mutant, a novel gene knock-in model in which Bmpr1a was expressed in the ACVR1 locus only partially restored septation in ACVR1 mutants. These data show that both BmpR1a and ACVR1 are needed for normal heart development, in which they play some non-redundant roles, and refine our understanding of the genetic and morphogenetic processes underlying Bmp-mediated heart development important in human congenital heart disease.
Yuji Mishina - One of the best experts on this subject based on the ideXlab platform.
-
activin a receptor type 1 mediated bmp signaling regulates rankl induced osteoclastogenesis via canonical smad signaling pathway
Journal of Biological Chemistry, 2019Co-Authors: Vesa Kaartinen, Yuji MishinaAbstract:Bone morphogenetic proteins (BMPs) are important mediators of osteoclast differentiation. Although accumulating evidence has implicated BMPs in osteoblastogenesis, the mechanisms by which BMPs regulate osteoclastogenesis remain unclear. Activin A receptor type 1 (ACVR1) is a BMP type 1 receptor essential for skeletal development. Here, we observed that BMP-7, which preferentially binds to ACVR1, promotes osteoclast differentiation, suggesting ACVR1 is involved in osteoclastogenesis. To investigate this further, we isolated osteoclasts from either ACVR1-floxed mice or mice with constitutively-activated ACVR1 (caACVR1) carrying tamoxifen-inducible Cre driven by a ubiquitin promotor and induced Cre activity in culture. Osteoclasts from the ACVR1-floxed mice had reduced osteoclast numbers and demineralization activity, whereas those from the caACVR1-mutant mice formed large osteoclasts and demineralized pits, suggesting that BMP signaling through ACVR1 regulates osteoclast fusion and activity. It is reported that BMP-2 binds to BMPR1A, another BMP type 1 receptor, whereas BMP-7 binds to ACVR1 to activate SMAD1/5/9 signaling. Here, Bmpr1a-disrupted osteoclasts displayed reduced phospho-SMAD1/5/9 (pSMAD1/5/9) levels when induced by BMP-2, whereas no impacts on pSMAD1/5/9 were observed when induced by BMP-7. In contract, ACVR1-disrupted osteoclasts displayed reduced pSMAD1/5/9 levels when induced either by BMP-2 or BMP-7, suggesting that ACVR1 is the major receptor for transducing BMP-7 signals in osteoclasts. Indeed, LDN-193189 and LDN-212854, which specifically block SMAD1/5/9 phosphorylation, inhibited osteoclastogenesis of caACVR1-mutant cells. Moreover, increased BMP signaling promoted nuclear translocation of nuclear factor-activated T-cells 1 (NFATc1), which was inhibited by LDN treatments. Taken together, ACVR1-mediated BMP-SMAD signaling activates NFATc1, a regulatory protein crucial for receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis.
-
ACVR1 is essential for periodontium development and promotes alveolar bone formation
Archives of Oral Biology, 2018Co-Authors: Xue Zhang, Yuji Mishina, Qilin Liu, Huan Zhao, Cangwei Liu, Guangxing Yan, Ce Shi, Hongchen SunAbstract:Abstract Objective To explore the role of a BMP type I receptor (ACVR1) in regulating periodontium development, ACVR1 was conditionally disrupted in Osterix-expressing cells. Methods Mandibles from both control (ACVR1 fx/+; Osterix-Cre (+)/(-)) and cKO (ACVR1 fx/-; Osterix-Cre (+)/(-)) mice at postnatal day 21 (PN21) were scanned by micro-CT, followed by decalcification and histological observations. Distributions and levels of differentiation markers of fibroblasts, osteoblasts and cementocytes in the periodontium were detected by immunohistochemical (IHC) staining. Results Micro-CT results showed that bone mass and bone mineral density of the alveolar bones in the cKO mice were lower than those in the controls. Histomorphometry within the alveolar bones revealed that the lower bone mass observed in the cKO mice was caused by increased numbers and resorption activities of osteoclasts. The markers for osteoblast differentiation, Col I and DMP1, were reduced and the signals of the RANKL/OPG ratio were increased in the alveolar bones of the cKO mice compared to those of the control mice. The periodontal ligament in the cKO mice exhibited disorganized collagen fibers with weaker signals of Col I and periostin. However, there was no difference in terms of the cellular cementum between the two groups. Conclusion ACVR1 is essential for normal periodontium development. ACVR1 in the osteoblasts negatively regulates osteoclast differentiation in association with the RANKL/OPG axis and thus promotes alveolar bone formation.
-
BmpR1A is a major type 1 BMP receptor for BMP-Smad signaling during skull development
Developmental biology, 2017Co-Authors: Haichun Pan, Vesa Kaartinen, Karen M Lyons, Honghao Zhang, Ponnu Abraham, Yuji MishinaAbstract:Craniosynostosis is caused by premature fusion of one or more sutures in an infant skull, resulting in abnormal facial features. The molecular and cellular mechanisms by which genetic mutations cause craniosynostosis are incompletely characterized, and many of the causative genes for diverse types of syndromic craniosynostosis have not yet been identified. We previously demonstrated that augmentation of BMP signaling mediated by a constitutively active BMP type IA receptor (ca-BmpR1A) in neural crest cells (ca1A hereafter) causes craniosynostosis and superimposition of heterozygous null mutation of Bmpr1a rescues premature suture fusion (ca1A;1aH hereafter). In this study, we superimposed heterozygous null mutations of the other two BMP type I receptors, Bmpr1b and ACVR1 (ca1A;1bH and ca1A;AcH respectively hereafter) to further dissect involvement of BMP-Smad signaling. Unlike caA1;1aH, ca1A;1bH and ca1A;AcH did not restore the craniosynostosis phenotypes. In our in vivo study, Smad-dependent BMP signaling was decreased to normal levels in mut;1aH mice. However, BMP receptor-regulated Smads (R-Smads; pSmad1/5/9 hereafter) levels were comparable between ca1A, ca1A;1bH and ca1A;AcH mice, and elevated compared to control mice. Bmpr1a, Bmpr1b and ACVR1 null cells were used to examine potential mechanisms underlying the differences in ability of heterozygosity for Bmpr1a vs. Bmpr1b or ACVR1 to rescue the mut phenotype. pSmad1/5/9 level was undetectable in Bmpr1a homozygous null cells while pSmad1/5/9 levels did not decrease in Bmpr1b or ACVR1 homozygous null cells. Taken together, our study indicates that different levels of expression and subsequent activation of Smad signaling differentially contribute each BMP type I receptor to BMP-Smad signaling and craniofacial development. These results also suggest differential involvement of each type 1 receptor in pathogenesis of syndromic craniosynostoses.
-
normal gonadotropin production and fertility in gonadotrope specific bmpr1a knockout mice
Journal of Endocrinology, 2016Co-Authors: Xiang Zhou, Vesa Kaartinen, Yuji Mishina, Ying Y Wang, Luisina Ongaro, Ulrich Boehm, Daniel J BernardAbstract:Pituitary follicle-stimulating hormone (FSH) synthesis is regulated by transforming growth factorβsuperfamily ligands, most notably the activins and inhibins. Bone morphogenetic proteins (BMPs) also regulate FSHβ subunit (Fshb) expression in immortalized murine gonadotrope-like LβT2 cells and in primary murine or ovine primary pituitary cultures. BMP2 signals preferentially via the BMP type I receptor, BMPR1A, to stimulate murine Fshb transcription in vitro Here, we used a Cre-lox approach to assess BMPR1A's role in FSH synthesis in mice in vivo Gonadotrope-specific Bmpr1a knockout animals developed normally and had reproductive organ weights comparable with those of controls. Knockouts were fertile, with normal serum gonadotropins and pituitary gonadotropin subunit mRNA expression. Cre-mediated recombination of the floxed Bmpr1a allele was efficient and specific, as indicated by PCR analysis of diverse tissues and isolated gonadotrope cells. Furthermore, BMP2 stimulation of inhibitor of DNA binding 3 expression was impaired in gonadotropes isolated from Bmpr1a knockout mice, confirming the loss of functional receptor protein in these cells. Treatment of purified gonadotropes with small-molecule inhibitors of BMPR1A (and the related receptors BMPR1B and ACVR1) suppressed Fshb mRNA expression, suggesting that an autocrine BMP-like molecule might regulate FSH synthesis. However, deletion of Bmpr1a and ACVR1 in cultured pituitary cells did not alter Fshb expression, indicating that the inhibitors had off-target effects. In sum, BMPs or related ligands acting via BMPR1A or ACVR1 are unlikely to play direct physiological roles in FSH synthesis by murine gonadotrope cells.
-
ACVR1 mediated bmp signaling in second heart field is required for arterial pole development implications for myocardial differentiation and regional identity
Developmental Biology, 2014Co-Authors: Penny S Thomas, Jamie Lane, Sudha Rajderkar, Yuji Mishina, Vesa KaartinenAbstract:BMP signaling plays an essential role in second heart field-derived heart and arterial trunk development, including myocardial differentiation, right ventricular growth, and interventricular, outflow tract and aortico-pulmonary septation. It is mediated by a number of different BMP ligands, and receptors, many of which are present simultaneously. The mechanisms by which they regulate morphogenetic events and degree of redundancy amongst them have still to be elucidated. We therefore assessed the role of BMP Type I receptor ACVR1 in anterior second heart field-derived cell development, and compared it with that of BmpR1a. By removing ACVR1 using the driver Mef2c[AHF]-Cre, we show that ACVR1 plays an essential role in arterial pole morphogenesis, identifying defects in outflow tract wall and cushion morphology that preceded a spectrum of septation defects from double outlet right ventricle to common arterial trunk in mutants. Its absence caused dysregulation in gene expression important for myocardial differentiation (Isl1, Fgf8) and regional identity (Tbx2, Tbx3, Tbx20, Tgfb2). Although these defects resemble to some degree those in the equivalent Bmpr1a mutant, a novel gene knock-in model in which Bmpr1a was expressed in the ACVR1 locus only partially restored septation in ACVR1 mutants. These data show that both BmpR1a and ACVR1 are needed for normal heart development, in which they play some non-redundant roles, and refine our understanding of the genetic and morphogenetic processes underlying Bmp-mediated heart development important in human congenital heart disease.
Nicholas P Legendre - One of the best experts on this subject based on the ideXlab platform.
-
activin dependent signaling in fibro adipogenic progenitors causes fibrodysplasia ossificans progressiva
Nature Communications, 2018Co-Authors: John B Leesshepard, Masakazu Yamamoto, Arpita A Biswas, Sean J Stoessel, Sarah Anne E Nicholas, Cathy Cogswell, Parvathi M Devarakonda, Michael J Schneider, Samantha M Cummins, Nicholas P LegendreAbstract:Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (ACVR1 tnR206H ). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type ACVR1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted ACVR1 R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.
-
Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Nature Publishing Group, 2018Co-Authors: John B. Lees-shepard, Masakazu Yamamoto, Arpita A Biswas, Sean J Stoessel, Sarah Anne E Nicholas, Cathy Cogswell, Parvathi M Devarakonda, Michael J Schneider, Samantha M Cummins, Nicholas P LegendreAbstract:Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice
David C Beebe - One of the best experts on this subject based on the ideXlab platform.
-
functions of the type 1 bmp receptor ACVR1 alk2 in lens development cell proliferation terminal differentiation and survival
Investigative Ophthalmology & Visual Science, 2008Co-Authors: Ramya Rajagopal, Vesa Kaartinen, David C Beebe, Lisa K. Dattilo, Chuxia Deng, Lieve Umans, An Zwijsen, Anita B Roberts, Erwin P BottingerAbstract:Lens formation is one of the most widely studied examples of embryonic induction. 1,2 As a result of the precise localization of cell proliferation and differentiation in the developing lens, it has often been used to demonstrate the fundamental molecular mechanisms that control terminal cell differentiation and cell proliferation in all tissues.3-6 Lens morphogenesis begins on embryonic day (E) 9 of mouse development with the formation of the lens placode. After the lens placode invaginates and separates from the surface ectoderm to form the lens vesicle, cells in the posterior part of the vesicle stop proliferating and form primary lens fiber cells. The anterior epithelial cells continue to proliferate. Proliferation eventually becomes restricted to the epithelial cells near the lens equator, which subsequently differentiate into secondary fiber cells, accounting for lens growth throughout life. Lens formation and its subsequent development are regulated by members of at least two major families of growth factors. Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-β (TGFβ) superfamily, are essential for lens induction. Targeted deletion or inactivation of the BMP ligands Bmp4 and Bmp7 results in the failure of lens formation.2,7-9 Lenses lacking the type 1 BMP receptor Bmpr1a (Alk3) are small, have thin epithelia, and degenerate fiber cells.10 Fibroblast growth factors (FGFs) are the other family of growth factors important for lens formation. Deletion of Fgfr2 results in defects in fiber cell terminal differentiation and reduced cell survival,11 and the deletion of Fgfr1, Fgfr2, and Fgfr3 in the lens vesicle prevents subsequent fiber cell formation.12 Finally, there is genetic evidence of interactions between the FGF and BMP signaling pathways during early lens development.13 Although BMPs are essential for lens development, little is known about the cellular events initiated by BMP signaling and the downstream signaling molecules that mediate these events during lens induction and subsequent development. The BMP signaling cascade is initiated by type 2 and type 1 cell surface serine/threonine kinase receptors. Ligand-activated receptors phosphorylate downstream signaling molecules, the receptor-activated Smads or R-Smads. Activated R-Smads complex with the common mediator Smad (Co-Smad) known as Smad4 and translocate to the nucleus to regulate gene expression.14 To gain an understanding of the molecular events mediating BMP signaling in the lens, we used the Cre-loxP approach to inactivate the type 1 BMP receptor ACVR1 (Alk2) in the lens-forming head ectoderm of the mouse embryo. ACVR1 is expressed in the prospective ectoderm at the time of lens induction,15 but its function in lens development has not been examined. ACVR1CKO (conditional knockout) lenses formed but were smaller than wild-type lenses. Analysis of the cause of the smaller lens size revealed that ACVR1 promoted proliferation at early stages (Rajagopal R et al., manuscript submitted) but inhibited epithelial cell proliferation later in lens development. Inhibition of cell proliferation by ACVR1 was necessary for the proper regionalization of the lens epithelium and promoted the withdrawal of lens fiber cells from the cell cycle. Deletion of the downstream Smad effector proteins showed that ACVR1 inhibited proliferation and promoted cell cycle exit by engaging the BMP-specific R-Smads (Smad1 and Smad5) and the Co-Smad (Smad4). Although ACVR1 is required for fiber cells to withdraw from the cell cycle, it is not required for the expression of proteins that are characteristic of differentiated fiber cells. ACVR1 signaling promoted the survival of lens epithelial and fiber cells. The initial decrease in proliferation, along with an increase in cell death in the ACVR1CKO lens epithelia and fiber cells, appears to account for the overall decrease in lens size.