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Richard M. Harland - One of the best experts on this subject based on the ideXlab platform.
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Noggin is required for first pharyngeal arch differentiation in the frog Xenopus tropicalis.
Developmental Biology, 2017Co-Authors: John J. Young, Rachel A. S. Kjolby, Daniel Wong, Shu-wei Hsu, Richard M. HarlandAbstract:The dorsal ventral axis of vertebrates requires high BMP activity for ventral development and inhibition of BMP activity for dorsal development. Presumptive dorsal regions of the embryo are protected from the ventralizing activity of BMPs by the secretion of BMP antagonists from the mesoderm. Noggin, one such antagonist, binds BMP ligands and prevents them from binding their receptors, however, a unique role for Noggin in amphibian development has remained unclear. Previously, we used zinc-finger nucleases to mutagenize the Noggin locus in Xenopus tropicalis. Here, we report on the phenotype of Noggin mutant frogs as a result of breeding null mutations to homozygosity. Early homozygous Noggin mutant embryos are indistinguishable from wildtype siblings, with normal neural induction and neural tube closure. However, in late tadpole stages mutants present severe ventral craniofacial defects, notably a fusion of Meckel’s cartilage to the palatoquadrate cartilage. Consistent with a Noggin loss-of-function, mutants show expansions of BMP target gene expression and the mutant phenotype can be rescued with transient BMP inhibition. These results demonstrate that in amphibians, Noggin is dispensable for early embryonic patterning but is critical for cranial skeletogenesis.
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follistatin interacts with Noggin in the development of the axial skeleton
Mechanisms of Development, 2014Co-Authors: David Stafford, Stefanie D Monica, Richard M. HarlandAbstract:When compared to single mutants for Follistatin or Noggin, we find that double mutants display a dramatic further reduction in trunk cartilage formation, particularly in the vertebral bodies and proximal ribs. Consistent with these observations, expression of the early sclerotome markers Pax1 and Uncx is diminished in Noggin;Follistatin compound mutants. In contrast, Sim1 expression expands medially in double mutants. As the onset of Follistatin expression coincides with sclerotome specification, we argue that the effect of Follistatin occurs after sclerotome induction. We hypothesize that Follistatin aids in maintaining proper somite size, and consequently sclerotome progenitor numbers, by preventing paraxial mesoderm from adopting an intermediate/lateral plate mesodermal fate in the Noggin-deficient state.
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Noggin suppression enhances in vitro osteogenesis and accelerates in vivo bone formation
Journal of Biological Chemistry, 2007Co-Authors: Derrick C. Wan, Lisa J Brunet, Richard M. Harland, Jason H. Pomerantz, Jae-beom Kim, Yu-fen Chou, Helen M. Blau, Michael T LongakerAbstract:Several investigations have demonstrated a precise balance to exist between bone morphogenetic protein (BMP) agonists and antagonists, dictating BMP signaling and osteogenesis. We report a novel approach to manipulate BMP activity through a down-regulation of the potent BMP antagonist Noggin, and examined the effects on the bone forming capacity of osteoblasts. Reduction of Noggin enhanced BMP signaling and in vitro osteoblast bone formation, as demonstrated by both gene expression profiles and histological staining. The effects of Noggin suppression on in vivo bone formation were also investigated using critical-sized calvarial defects in mice repaired with Noggin-suppressed osteoblasts. Radiographic and histological analyses revealed significantly more bone regeneration at 2 and 4 weeks post-injury. These findings strongly support the concept of enhanced osteogenesis through a down-regulation in Noggin and suggest a novel approach to clinically accelerate bone formation, potentially allowing for earlier mobilization of patients following skeletal injury or surgical resection.
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the bmp antagonist Noggin regulates cranial suture fusion
Nature, 2003Co-Authors: Stephen M Warren, Lisa J Brunet, Richard M. Harland, Aris N Economides, Michael T LongakerAbstract:During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates1. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex2. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation3. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors (fgfr) are associated with syndromic forms of craniosynostosis4,5. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning6,7,8. Here we show that Noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that Noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since Noggin misexpression prevents cranial suture fusion in vitro and in vivo, we suggest that syndromic fgfr-mediated craniosynostoses may be the result of inappropriate downregulation of Noggin expression.
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Human disease-causing NOG missense mutations: effects on Noggin secretion, dimer formation, and bone morphogenetic protein binding.
Proceedings of the National Academy of Sciences, 2001Co-Authors: Jose Marcelino, Richard M. Harland, Aris N Economides, Christopher M. Sciortino, Michael F. Romero, Lynn Ulatowski, R. Tracy Ballock, Peter M. Eimon, Matthew L. WarmanAbstract:Abstract Secreted Noggin protein regulates bone morphogenetic protein activity during development. In mice, a complete loss of Noggin protein leads to multiple malformations including joint fusion, whereas mice heterozygous for Nog loss-of-function mutations are normal. In humans, heterozygous NOG missense mutations have been found in patients with two autosomal dominant disorders of joint development, multiple synostosis syndrome (SYNS1) and a milder disorder proximal symphalangism (SYM1). This study investigated the effect of one SYNS1 and two SYM1 disease-causing missense mutations on the structure and function of Noggin. The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional Noggin dimers in transiently transfected COS-7 cells. Coexpression of mutant Noggin with wild-type Noggin, to resemble the heterozygous state, did not interfere with wild-type Noggin secretion. These data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric Noggin. Therefore, we conclude that Noggin has both species-specific and joint-specific dosage-dependent roles during joint formation. Surprisingly, in contrast to the COS-7 cell studies, the SYNS1 mutant was able to form dimers in Xenopus laevis oocytes. This finding indicates that there also exist species-specific differences in the ability to process mutant Noggin polypeptides.
Aris N Economides - One of the best experts on this subject based on the ideXlab platform.
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structural basis of bmp signaling inhibition by Noggin a novel twelve membered cystine knot protein
Journal of Bone and Joint Surgery American Volume, 2003Co-Authors: Jay Groppe, Witek Kwiatkowski, Jason Greenwald, Ezra Wiater, Markus Affolter, Aris N Economides, Joaquin Rodriguezleon, Kandan Baban, Wylie Vale, Juan Carlos Izpisua BelmonteAbstract:Background: The activity of bone morphogenetic proteins (BMPs) is regulated extracellularly by several families of secreted, negatively-acting factors. These BMP antagonists participate in the control of a diverse range of embryonic processes, such as establishment of the dorsal-ventral axis, neural induction, and formation of joints in the developing skeletal system. The ongoing process of neurogenesis in the adult brain also requires inhibition of BMP ligand activity. To date, the three-dimensional structures of these antagonists as well as the nature of their interaction with ligand have remained unknown. Toward that end, we have determined the crystal structure of the antagonist Noggin bound to BMP-7. Methods: The complex of the two homodimeric proteins was preformed, isolated by size exclusion chromatography, and crystallized at neutral pH. To probe the molecular interface of the complex and to quantitate the activity of a human mutant form, variant Noggin proteins were produced and their binding affinities were measured in vitro. The correlation between binding affinity and biological activity was examined with Noggin-soaked beads implanted in the developing chick limb bud. Results and Conclusions: The structure of the complex reveals that Noggin inhibits BMP signaling by blocking the binding sites of both types of receptors (Type I and Type II), mimicking their modes of binding. The affinity of Noggin variants for BMP-7 correlated well with the inhibition of BMP-induced chondrogenesis in the chick limb bud, confirming that Noggin acts by sequestering the ligand in an inactive state. Interestingly, the scaffold of Noggin was found to contain a cystine knot topology and protein fold similar to that of BMPs, indicating that ligand and antagonist may have evolved from a common ancestral gene. Clinical Relevance: Mutations in the human Noggin locus (NOG) are associated with three similar yet distinct skeletal dysplasias: proximal symphalangism (SYM1), multiple synostoses syndrome (SYNS1), and tarsal-carpal coalition syndrome (TCC). The crystal structure of the Noggin:BMP-7 complex provides a structural context for interpreting the effects of missense mutations with respect to Noggin protein folding, stability, or activity. The structure also provides the basis for engineering variants of Noggin that may have therapeutic applications in the treatment of fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of connective tissue resulting from lymphocytic misexpression of BMPs.
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the bmp antagonist Noggin regulates cranial suture fusion
Nature, 2003Co-Authors: Stephen M Warren, Lisa J Brunet, Richard M. Harland, Aris N Economides, Michael T LongakerAbstract:During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates1. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex2. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation3. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors (fgfr) are associated with syndromic forms of craniosynostosis4,5. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning6,7,8. Here we show that Noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that Noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since Noggin misexpression prevents cranial suture fusion in vitro and in vivo, we suggest that syndromic fgfr-mediated craniosynostoses may be the result of inappropriate downregulation of Noggin expression.
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Skeletal Overexpression of Noggin Results in Osteopenia and Reduced Bone Formation
Endocrinology, 2003Co-Authors: R. D. Devlin, Aris N Economides, R.c. Pereira, R. B. Kimble, Vanda JorgettiAbstract:Skeletal cells synthesize bone morphogenetic proteins (BMPs) and BMP antagonists. Noggin is a glycoprotein that binds BMPs selectively and antagonizes BMP actions. Noggin expression in osteoblasts is induced by BMPs and Noggin opposes the effects of BMPs on osteoblastic differentiation and function in vitro. However, its effects in vivo are not known. We investigated the direct in vivo effects of Noggin on bone remodeling in transgenic mice overexpressing Noggin under the control of the osteocalcin promoter. Noggin transgenics suffered long bone fractures in the first month of life. Total, vertebral, and femoral bone mineral densities were reduced by 23-29%. Static and dynamic histomorphometry of the femur revealed that Noggin transgenic mice had decreased trabecular bone volume, number of trabeculae, and bone formation rate. Osteoblast surface and number of osteoblasts/trabecular area were not significantly decreased, indicating impaired osteoblastic function. Osteoclast surface and number were normal/decreased, there was no increase in bone resorption, and the tissue had the appearance of woven bone. Vertebral microcomputed tomography scanning confirmed decreased trabecular bone volume and trabecular number. In conclusion, transgenic mice overexpressing Noggin in the bone microenvironment have decreased trabecular bone volume and impaired osteoblastic function, leading to osteopenia and fractures.
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heparan sulfate proteoglycans retain Noggin at the cell surface a potential mechanism for shaping bone morphogenetic protein gradients
Journal of Biological Chemistry, 2002Co-Authors: Stephenie Painesaunders, Aris N Economides, Beth L Viviano, Scott SaundersAbstract:Bone morphogenetic proteins (BMPs) are expressed broadly and regulate a diverse array of developmental events in vivo. Essential to many of these functions is the establishment of activity gradients of BMP, which provide positional information that influences cell fates. Secreted polypeptides, such as Noggin, bind BMPs and inhibit their function by preventing interaction with receptors on the cell surface. These BMP antagonists are assumed to be diffusible and therefore potentially important in the establishment of BMP activity gradients in vivo. Nothing is known, however, about the potential interactions between Noggin and components of the cell surface or extracellular matrix that might limit its diffusion. We have found that Noggin binds strongly to heparin in vitro, and to heparan sulfate proteoglycans on the surface of cultured cells. Noggin is detected only on the surface of cells that express heparan sulfate, can be specifically displaced from cells by heparin, and can be directly cross-linked to a cell surface proteoglycan in culture. Heparan sulfate-bound Noggin remains functional and can bind BMP4 at the plasma membrane. A Noggin mutant with a deletion in a putative heparin binding domain has reduced binding to heparin and does not bind to the cell surface but has preserved BMP binding and antagonist functions. Our results imply that interactions between Noggin and heparan sulfate proteoglycans in vivo regulate diffusion and therefore the formation of gradients of BMP activity.
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Structural basis of BMP signalling inhibition by the cystine knot protein Noggin
Nature, 2002Co-Authors: Jay Groppe, Witek Kwiatkowski, Wylie W. Vale, Juan Carlos Izpisúa-belmonte, Jason Greenwald, Ezra Wiater, Markus Affolter, Joaquín Rodríguez-león, Aris N Economides, Senyon ChoeAbstract:The interplay between bone morphogenetic proteins (BMPs) and their antagonists governs developmental and cellular processes as diverse as establishment of the embryonic dorsal-ventral axis, induction of neural tissue, formation of joints in the skeletal system and neurogenesis in the adult brain. So far, the three-dimensional structures of BMP antagonists and the structural basis for inactivation have remained unknown. Here we report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. The BMP-7-binding affinity of site-specific variants of Noggin is correlated with alterations in bone formation and apoptosis in chick limb development, showing that Noggin functions by sequestering its ligand in an inactive complex. The scaffold of Noggin contains a cystine (the oxidized form of cysteine) knot topology similar to that of BMPs; thus, ligand and antagonist seem to have evolved from a common ancestral gene.
John Klingensmith - One of the best experts on this subject based on the ideXlab platform.
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bmp antagonism by Noggin is required in presumptive notochord cells for mammalian foregut morphogenesis
Developmental Biology, 2014Co-Authors: Sarah R Fausett, Lisa J Brunet, John KlingensmithAbstract:Esophageal atresia with tracheoesophageal fistula (EA/TEF) is a serious human birth defect, in which the esophagus ends before reaching the stomach, and is aberrantly connected with the trachea. Several mouse models of EA/TEF have recently demonstrated that proper dorsal/ventral (D/V) patterning of the primitive anterior foregut endoderm is essential for correct compartmentalization of the trachea and esophagus. Here we elucidate the pathogenic mechanisms underlying the EA/TEF that occurs in mice lacking the BMP antagonist Noggin, which display correct dorsal/ventral patterning. To clarify the mechanism of this malformation, we use spatiotemporal manipulation of Noggin and BMP receptor 1A conditional alleles during foregut development. Surprisingly, we find that the expression of Noggin in the compartmentalizing endoderm is not required to generate distinct tracheal and esophageal tubes. Instead, we show that Noggin and BMP signaling attenuation are required in the early notochord to correctly resolve notochord cells from the dorsal foregut endoderm, which in turn, appears to be a prerequisite for foregut compartmentalization. Collectively, our findings support an emerging model for a mechanism underlying EA/TEF in which impaired notochord resolution from the early endoderm causes the foregut to be hypo-cellular just prior to the critical period of compartmentalization. Our further characterizations suggest that Noggin may regulate a cell rearrangement process that involves reciprocal E-cadherin and Zeb1 expression in the resolving notochord cells.
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rna binding protein fxr2 regulates adult hippocampal neurogenesis by reducing Noggin expression
Neuron, 2011Co-Authors: Weixiang Guo, John Klingensmith, Li Zhang, Devin M Christopher, Zhaoqian Teng, Sarah R Fausett, Changmei Liu, Olivia L George, Peng Jin, Xinyu ZhaoAbstract:In adult mammalian brains, neurogenesis persists in the subventricular zone of the lateral ventricles (SVZ) and the dentate gyrus (DG) of the hippocampus. Although evidence suggest that adult neurogenesis in these two regions is subjected to differential regulation, the underlying mechanism is unclear. Here, we show that the RNA-binding protein FXR2 specifically regulates DG neurogenesis by reducing the stability of Noggin mRNA. FXR2 deficiency leads to increased Noggin expression and subsequently reduced BMP signaling, which results in increased proliferation and altered fate specification of neural stem/progenitor cells in DG. In contrast, Noggin is not regulated by FXR2 in the SVZ, because Noggin expression is restricted to the ependymal cells of the lateral ventricles, where FXR2 is not expressed. Differential regulation of SVZ and DG stem cells by FXR2 may be a key component of the mechanism that governs the different neurogenic processes in these two adult germinal zones.
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Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis.
Developmental Biology, 2010Co-Authors: Wei Xiong, John Klingensmith, Ying Wang, Maiko Matsui, Yang Chai, Yiping ChenAbstract:BMP signaling plays many important roles during organ development, including palatogenesis. Loss of BMP signaling leads to cleft palate formation. During development, BMP activities are finely tuned by a number of modulators at the extracellular and intracellular levels. Among the extracellular BMP antagonists is Noggin, which preferentialy binds to BMP2, BMP4 and BMP7, all of which are expressed in the developing palatal shelves. Here we use targeted Noggin mutant mice as a model for gain of BMP signaling function to investigate the role of BMP signaling in palate development. We find prominent Noggin expression in the palatal epithelium along the anterior-posterior axis during early palate development. Loss of Noggin function leads to overactive BMP signaling, particularly in the palatal epithelium. This results in disregulation of cell proliferation, excessive cell death, and changes in gene expression, leading to formation of complete palatal cleft. The excessive cell death in the epithelium disrupts the palatal epithelium integrity, which in turn leads to an abnormal palate-mandible fusion and prevents palatal shelf elevation. This phenotype is recapitulated by ectopic expression of a constitutively active form of BMPR-IA but not BMPR-IB in the epithelium of the developing palate; this suggests a role for BMPR-IA in mediating overactive BMP signaling in the absence of Noggin. Together with the evidence that overexpression of Noggin in the palatal epithelium does not cause a cleft palate defect, we conclude from our results that Noggin mediated modulation of BMP signaling is essential for palatal epithelium integrity and for normal palate development.
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The bone morphogenetic protein antagonist Noggin regulates mammalian cardiac morphogenesis
Circulation Research, 2007Co-Authors: Murim Choi, Rolf W. Stottmann, Yu-ping Yang, Erik N Meyers, John KlingensmithAbstract:Bone morphogenetic proteins (BMPs) play many roles in mammalian cardiac development. Here we address the functions of Noggin, a dedicated BMP antagonist, in the developing mouse heart. In early cardiac tissues, the Noggin gene is mainly expressed in the myocardial cells of the outflow tract, atrioventricular canal, and future right ventricle. The major heart phenotypes of Noggin mutant embryos are thicker myocardium and larger endocardial cushions. Both defects result from increased cell number. Cell proliferation is increased and cell cycle exit is decreased in the myocardium. Although we find evidence of increased BMP signal transduction in the myocardium and endocardium, we show that the cardiac defects of Noggin mutants are rescued by halving the gene dosage of Bmp4. In culture, BMP increases the epithelial-to-mesenchymal transformation (EMT) of endocardial explant cells. Increased EMT likely accounts for the enlarged atrioventricular cushion. In the outflow tract cushion, we observed an increased contribution of cardiac neural crest cells to the mutant cushion mesenchyme, although many cells of the cushion were not derived from neural crest. Thus the enlarged outflow tract cushion of Noggin mutants likely arises by increased contributions both of endocardial cells that have undergone EMT as well as cells that have migrated from the neural crest. These data indicate that antagonism of BMP signaling by Noggin plays a critical role in ensuring proper levels of cell proliferation and EMT during cardiac morphogenesis in the mouse.
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the bmp antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms
Developmental Biology, 2006Co-Authors: Rolf W. Stottmann, Murim Choi, Mark Berrong, Karen M Matta, John KlingensmithAbstract:Here we characterize the consequences of elevated bone morphogenetic protein (BMP) signaling on neural tube morphogenesis by analyzing mice lacking the BMP antagonist, Noggin. Noggin is expressed dorsally in the closing neural folds and ventrally in the notochord and somites. All Noggin−/− pups are born with lumbar spina bifida; depending on genetic background, they may also have exencephaly. The exencephaly is due to a primary failure of neurulation, resulting from a lack of mid/hindbrain dorsolateral hinge point (DLHP) formation. Thus, as previously shown for Shh signaling at spinal levels, BMP activity may inhibit cranial DLHP morphogenesis. However, the increased BMP signaling observed in the Noggin−/− dorsal neural tube is not sufficient to cause exencephaly; it appears to also depend on the action of a genetic modifier, which may act to increase dorsal Shh signaling. The spinal neural tube defect results from a different mechanism: increased BMP signaling in the mesoderm between the limb buds leads to abnormal somite differentiation and axial skeletal malformation. The resulting lack of mechanical support for the neural tube causes spina bifida. We show that this defect is due to elevated BMP4 signaling. Thus, Noggin is required for mammalian neurulation in two contexts, dependent on position along the rostrocaudal axis.
Chaya Kalcheim - One of the best experts on this subject based on the ideXlab platform.
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canonical wnt activity regulates trunk neural crest delamination linking bmp Noggin signaling with g1 s transition
Development, 2004Co-Authors: Tal Burstyncohen, Dalit Seladonenfeld, Jonathan Stanleigh, Chaya KalcheimAbstract:Delamination of premigratory neural crest cells depends on a balance between BMP/Noggin and on successful G1/S transition. Here, we report that BMP regulates G1/S transition and consequent crest delamination through canonical Wnt signaling. Noggin overexpression inhibits G1/S transition and blocking G1/S abrogates BMP-induced delamination; moreover, transcription of Wnt1 is stimulated by BMP and by the developing somites, which concomitantly inhibit Noggin production. Interfering with β-catenin and LEF/TCF inhibits G1/S transition, neural crest delamination and transcription of various BMP-dependent genes, which include Cad6B, Pax3 and Msx1, but not that of Slug, Sox9 or FoxD3. Hence, we propose that developing somites inhibit Noggin transcription in the dorsal tube, resulting in activation of BMP and consequent Wnt1 production. Canonical Wnt signaling in turn stimulates G1/S transition and generation of neural crest cell motility independently of its proposed role in earlier neural crest specification.
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inhibition of Noggin expression in the dorsal neural tube by somitogenesis a mechanism for coordinating the timing of neural crest emigration
Development, 2000Co-Authors: Dalit Seladonenfeld, Chaya KalcheimAbstract:We have previously shown that axial-dependent delamination of specified neural crest cells is triggered by BMP4 and negatively regulated by Noggin. Increasing activity of BMP4 towards the rostral part of the axis is achieved by graded expression of Noggin in the dorsal neural tube, the latter being high opposite unsegmented mesoderm, and progressively downregulated facing epithelial and dissociating somites, coinciding in time and axial level with initial delamination of neural crest cells (Sela-Donenfeld, D. and Kalcheim, C. (1999) Development 126, 4749-4762). Here we report that this gradient-like expression of Noggin in the neuroepithelium is controlled by the paraxial mesoderm. Deletion of epithelial somites prevented normal downregulation of Noggin in the neural tube. Furthermore, partial ablation of either the dorsal half or only the dorsomedial portion of epithelial somites was sufficient to maintain high Noggin expression. In contrast, deletion of the segmental plate had no effect. These data suggest that the dorsomedial region of developing somites produces an inhibitor of Noggin transcription in the dorsal neural tube. Consistent with this notion, grafting dissociating somites in the place of the unsegmented mesoderm precociously downregulated the expression of Noggin and triggered premature emigration of neural crest progenitors from the caudal neural tube. Thus, opposite the unsegmented mesoderm, where Noggin expression is high in the neural tube, BMP4 is inactive and neural crest cells fail to delaminate. Upon somitogenesis and further dissociation, the dorsomedial portion of the somite inhibits Noggin transcription. Progressive loss of Noggin activity releases BMP4 from inhibition, resulting in crest cell emigration. We propose that this inhibitory crosstalk between paraxial mesoderm and neural primordium controls the timing of neural crest delamination to match the development of a suitable mesodermal substrate for subsequent crest migration.
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regulation of the onset of neural crest migration by coordinated activity of bmp4 and Noggin in the dorsal neural tube
Development, 1999Co-Authors: Dalit Seladonenfeld, Chaya KalcheimAbstract:For neural crest cells to engage in migration, it is necessary that epithelial premigratory crest cells convert into mesenchyme. The mechanisms that trigger cell delamination from the dorsal neural tube remain poorly understood. We find that, in 15- to 40-somite-stage avian embryos, BMP4 mRNA is homogeneously distributed along the longitudinal extent of the dorsal neural tube, whereas its specific inhibitor Noggin exists in a gradient of expression that decreases caudorostrally. This rostralward reduction in signal intensity coincides with the onset of emigration of neural crest cells. Hence, we hypothesized that an interplay between Noggin and BMP4 in the dorsal tube generates graded concentrations of the latter that in turn triggers the delamination of neural crest progenitors. Consistent with this suggestion, disruption of the gradient by grafting Noggin-producing cells dorsal to the neural tube at levels opposite the segmental plate or newly formed somites, inhibited emigration of HNK-1-positive crest cells, which instead accumulated within the dorsal tube. Similar results were obtained with explanted neural tubes from the same somitic levels exposed to Noggin. Exposure to Follistatin, however, had no effect. The Noggin-dependent inhibition was overcome by concomitant treatment with BMP4, which when added alone, also accelerated cell emigration compared to untreated controls. Furthermore, the observed inhibition of neural crest emigration in vivo was preceded by a partial or total reduction in the expression of cadherin-6B and rhoB but not in the expression of slug mRNA or protein. Altogether, these results suggest that a coordinated activity of Noggin and BMP4 in the dorsal neural tube triggers delamination of specified, slug-expressing neural crest cells. Thus, BMPs play multiple and discernible roles at sequential stages of neural crest ontogeny, from specification through delamination and later differentiation of specific neural crest derivatives.
Scott Saunders - One of the best experts on this subject based on the ideXlab platform.
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domain specific modification of heparan sulfate by qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin
Journal of Biological Chemistry, 2004Co-Authors: Beth L Viviano, Stephenie Painesaunders, Nijole Gasiunas, John T Gallagher, Scott SaundersAbstract:We have reported previously that Noggin is a heparin-binding protein and associates with the cell surface through heparan sulfate proteoglycans, where it remains functional for the binding of bone morphogenetic proteins (BMPs). Here we report that the binding of Noggin to the cell surface is highly selective for heparan sulfate and that specific structural features are required for the interaction. Noggin binds most efficiently to heparin sequences composed of 10 or more monosaccharides; N-, 6-O-, and 2-O-sulfates contribute to this interaction. In addition, we have shown that the developmentally regulated endosulfatase Qsulf1 selectively removes sulfate groups from the 6-O position of sugars within the most highly sulfated S domains of heparan sulfate, whereas 6-O-sulfates in the NA/NS domains are not substrates for the enzyme. The activity of Qsulf1 in cells in culture results in the release of Noggin from the cell surface and a restoration of BMP responsiveness to the cells. This shows that Noggin binds to the S domains of heparan sulfate and provides evidence that, in addition to modulating Wnt signaling in vivo by the release of heparan sulfate bound Wnt, Qsulf1 also modulates BMP signaling by the release of surface-bound Noggin.
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heparan sulfate proteoglycans retain Noggin at the cell surface a potential mechanism for shaping bone morphogenetic protein gradients
Journal of Biological Chemistry, 2002Co-Authors: Stephenie Painesaunders, Aris N Economides, Beth L Viviano, Scott SaundersAbstract:Bone morphogenetic proteins (BMPs) are expressed broadly and regulate a diverse array of developmental events in vivo. Essential to many of these functions is the establishment of activity gradients of BMP, which provide positional information that influences cell fates. Secreted polypeptides, such as Noggin, bind BMPs and inhibit their function by preventing interaction with receptors on the cell surface. These BMP antagonists are assumed to be diffusible and therefore potentially important in the establishment of BMP activity gradients in vivo. Nothing is known, however, about the potential interactions between Noggin and components of the cell surface or extracellular matrix that might limit its diffusion. We have found that Noggin binds strongly to heparin in vitro, and to heparan sulfate proteoglycans on the surface of cultured cells. Noggin is detected only on the surface of cells that express heparan sulfate, can be specifically displaced from cells by heparin, and can be directly cross-linked to a cell surface proteoglycan in culture. Heparan sulfate-bound Noggin remains functional and can bind BMP4 at the plasma membrane. A Noggin mutant with a deletion in a putative heparin binding domain has reduced binding to heparin and does not bind to the cell surface but has preserved BMP binding and antagonist functions. Our results imply that interactions between Noggin and heparan sulfate proteoglycans in vivo regulate diffusion and therefore the formation of gradients of BMP activity.