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Results for “Noggin Protein”

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At least 19 recordsLinked to original sources

PubMed1993

Secreted noggin protein mimics the Spemann organizer in dorsalizing Xenopus mesoderm.

A dorsalizing signal acts during gastrulation to change the specification of lateral mesodermal tissues from ventral (blood, mesenchyme) to more dorsal fates (muscle, heart, pronephros). This signal, from Spemann's organizer, cannot be mimicked by the mesoderm inducers activin and fibroblast growth factor. The gene noggin is expressed in the organizer, and could be the dorsalizing signal. Here we show that soluble noggin protein added to ventral marginal zones during gastrulation induces muscle, but that activin does not. Dorsal pattern can be partially rescued in ventralized embryos by injection of a plasmid that expresses noggin during gastrulation. The results suggest that the noggin product may be the dorsalizing signal from the organizer.

Activins↗

PubMed2002

Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.

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.

Amino Acid Sequence↗

PubMed2005

Critical role of Cys168 in noggin protein's biological function.

Previous studies have indicated that noggin exerts its neural inducing effect by binding and antagonizing bone morphogenetic protein 4 (BMP4). In order to further clarify the relationship between the structure and the function of noggin, and elucidate the possible mechanism responsible for noggin-BMP4 interaction, we generated three noggin mutants, C168S, C174S and C197S, by using a site-directed mutagenesis method. Ectopic expression of wild-type (WT) noggin, C174S or C197S, in Xenopus animal caps (ACs) by mRNA injection converted the explants (prospective ectoderm) into neural tissue, as indicated by the neural-like morphology and expression of the neural cell adhesion molecule (NCAM) in the ACs. In contrast, ACs expressing C168S suffered an epidermal fate similar to the control caps. Similarly, among the three mutants, only C168S lost the dorsalizing function. These studies highlight the critical role played by Cys168 in noggin's biological activities. It probably participates in the formation of an intermolecular disulfide bridge.

Amino Acid Substitution↗

PubMed2002

The bone morphogenetic protein antagonist Noggin is regulated by Sox9 during endochondral differentiation.

Noggin has been described to be capable of binding bone morphogenetic proteins (BMP) and inhibiting BMP signaling by preventing the interactions of BMP with their receptors. Noggin expression during endochondral differentiation was analyzed to elucidate its potential role during chondrogenesis. Throughout mouse development, Noggin was expressed abundantly in the chondrocytic lineage as early as collagen type II RNA was detectable. In addition, a strong correlation was detected between Noggin expression and the expression profile of Sox9 during chondrogenesis. Sox9 (known to play an important role during chondrogenesis) and Noggin expression were investigated in the pluripotent mesenchymal cell line C3H10T1/2, stimulated by BMP-2. BMP-2 caused significant upregulation of Sox9 and Noggin expression in these cells. The upregulation of Noggin could be inhibited by introducing antisense oligonucleotides against Sox9 mRNA into the cells. Using mouse limb bud cultures, the role of Sox9 and Noggin during endochondral tissue differentiation was further studied. Treatment of cultures with Sox9 antisense oligonucleotides and/or Noggin protein caused significant alterations in limb morphogenesis and endochondral development. The data suggest that the transcriptional control of Noggin by Sox9 is a potent regulatory mechanism in chondrocyte differentiation.

Animals↗

PubMed2001

The bone morphogenetic proteins antagonist Noggin inhibits membranous ossification.

Bone morphogenetic proteins (BMPs) are expressed and secreted during fracture repair. Although they are likely to be required for this process, little is known about their physiological role in bone regeneration. Noggin is a protein that specifically binds and inactivates several BMPs. It plays fundamental roles during early embryonal development and limb morphogenesis by this BMP-inactivating activity. This study shows that Noggin can modify bone formation in vivo in the adult animal and, thus, indirectly, that BMP signaling is indispensable in this process. A noggin mutein (hNgdeltaB2-Fc) engineered so as to display increased bioavailability was used. Bilateral titanium bone chambers were inserted in 70 rats, and side comparisons for bone formation in the chambers were done. The hNgdeltaB2-Fc had no effect on total amount of tissue formed in the chamber but decreased the amount of bone compared with both buffer controls and a control made up of an Fc-tagged IL-6Ralpha protein, which had no effects of its own. Also, wild-type noggin inhibited bone formation. Thus, endogenous BMP signaling is necessary for normal bone regeneration.

Animals↗

PubMed2006

Bone morphogenetic proteins and noggin: inhibiting and inducing fungiform taste papilla development.

Fungiform papillae are epithelial specializations that develop in a linear pattern on the anterior mammalian tongue and differentiate to eventually contain taste buds. Little is known about morphogenetic and pattern regulation of these crucial taste organs. We used embryonic rat tongue, organ cultures to test roles for bone morphogenetic proteins, BMP2, 4 and 7, and antagonists noggin and follistatin, in development of papillae from a stage before morphological initiation (E13) or from a stage after the pre-papilla placodes have formed (E14). BMPs and noggin proteins become progressively restricted to papilla locations during tongue development. In E13 cultures, exogenous BMPs or noggin induce increased numbers of fungiform papillae, in a concentration-dependent manner, compared to standard tongue cultures; BMPs, but not noggin, lead to a decreased tongue size at this stage. In E14 cultures, however, exogenous BMP2, 4 or 7 each inhibits papilla formation so that there is a decrease in papilla number. Noggin substantially increases number of papillae in E14 cultures. Using beads for a highly localized protein delivery, papillae are inhibited in the surround of BMP-soaked beads and induced in large clusters around noggin-soaked beads. Follistatin, presented in culture medium or by bead, does not alter papilla formation or number. In all fungiform papillae that form under various culture conditions, the molecular marker, sonic hedgehog, is within each papilla. However, the BMP inhibitory effect on papillae is not prevented by disrupting sonic hedgehog signaling through addition of cyclopamine to cultures. BMPs and noggin alter cell proliferation in tongue epithelium in opposite ways, demonstrated with Ki67 immunostaining. We propose that the BMPs and noggin, colocalized within papilla placodes and the fungiform papillae per se, have opposing inhibitory and activating or inducing roles in papilla development in linear patterns. We present a model for these effects.

Animals↗

PubMed2006

Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the bone morphogenic protein antagonist noggin.

It is currently not known whether dopamine (DA) neurons derived from human embryonic stem cells (hESCs) can survive in vivo and alleviate symptoms in models of Parkinson disease (PD). Here, we report the use of Noggin (a bone morphogenic protein antagonist) to induce neuroectodermal cell development and increase the yield of DA neurons from hESCs. A combination of stromal-derived inducing activity and Noggin markedly enhanced the generation of neuroepithelial progenitors that could give rise to DA neurons. In addition, Noggin diminished the occurrence of a fibroblast-like Nestin-positive precursor population that differentiated into myocytes. After transplantation of differentiated hESCs to a rodent model of PD, some grafts contained human midbrain-like DA neurons. This protocol demonstrates hESC derivation and survival of human DA neurons appropriate for cell therapy in PD.

Animals↗

PubMed2003

Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin.

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.

Animals↗

PubMed2007

The bone morphogenetic protein antagonist noggin regulates mammalian cardiac morphogenesis.

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.

Animals↗

PubMed1997

Mechanisms of dorsal-ventral patterning in noggin-induced neural tissue.

We have investigated mechanisms of dorsal-ventral patterning of neural tissue, using Xenopus ectoderm neuralized by noggin protein. This tissue appears to be patterned dorsoventrally; cp1-1, a gene expressed in the dorsal brain, and etr-1, a gene largely excluded from the dorsal brain, are expressed in separate territories in noggin-treated explants (Knecht, A. K., Good, P. J., Dawid, I. B. and Harland, R. M. (1995) Development 121, 1927-1936). Here we show further evidence that this pattern represents a partial dorsal-ventral organization. Additionally, we test two mechanisms that could account for this pattern: a dose-dependent response to a gradient of noggin protein within the explant, and regulative cell-cell interactions. We show that noggin exhibits concentration-dependent effects, inducing cp1-1 at low doses but repressing it at high doses. Since noggin acts by antagonizing Bone Morphogenetic Protein (BMP) signaling, this result suggests that BMPs also may act in a dose-dependent manner in vivo. However, in the absence of a noggin gradient, regulative cell-cell interactions can also pattern the tissue. Such regulation is facilitated by increased motility of noggin-treated cells. Finally, the response of cells to both of these patterning mechanisms is ultimately controlled by a third process, the changing competence of the responding tissue.

Animals↗

PubMed1994

Specification of mesodermal pattern in Xenopus laevis by interactions between Brachyury, noggin and Xwnt-8.

We demonstrate that the nuclear, sequence-specific DNA-binding protein Xbra causes dorsal mesodermal differentiation of animal cap ectoderm when co-expressed with the secreted proteins noggin and Xwnt-8. None of these molecules causes dorsal mesoderm formation when expressed alone. Co-expression of Xenopus Brachyury (Xbra) mRNA with noggin mRNA in animal caps specifies the main dorsal tissues, namely muscle, notochord and neural tissue. Co-expression of Xbra with Xwnt-8, in contrast, converts animal caps to muscle masses. We have previously shown that expression of Xbra alone in animal caps is sufficient to specify ventral mesoderm which expresses Xhox3 and low levels of muscle-specific actin. We now conclude that the putative transcription factor Xbra defines a cell state in the vertebrate embryo which can respond to diffusible dorsal signals such as noggin and Xwnt-8, resulting in dorsal mesodermal differentiation. In the absence of such dorsal signals Xbra causes ventral mesodermal differentiation. This state is only partially maintained after the mid-blastula transition as it permits the dorsal response to zygotically expressed noggin but it does not allow a dorsal response to zygotically expressed Xwnt-8, which elicits only ventral mesodermal differentiation.

Animals↗

PubMed2002

Significance of bone morphogenetic protein-4 function in the initial myofibrillogenesis of chick cardiogenesis.

The heart is the first organ to form and function during vertebrate embryogenesis. Using a secreted protein, noggin, which specifically antagonizes bone morphogenetic protein (BMP)-2 and -4, we examined the role played by BMP during the initial myofibrillogenesis in chick cultured precardiac mesoendoderm (mesoderm + endoderm; ME). Conditioned medium from COS7 cells transfected with Xenopus noggin cDNA inhibited the expression of sarcomeric proteins (such as sarcomeric alpha-actinin, Z-line titin, and sarcomeric myosin), and so myofibrillogenesis was perturbed in cultured stage 4 precardiac ME; however, it did not inhibit the expression of smooth muscle alpha-actin (the first isoform of alpha-actin expressed during cardiogenesis). In cultured stage 5 precardiac ME, noggin did not inhibit either the formation of I-Z-I components or the expression of sarcomeric myosin, but it did inhibit the formation of A-bands. Although BMP4 was required to induce expressions of sarcomeric alpha-actinin, titin, and sarcomeric myosin in cultured stage 6 posterolateral mesoderm (noncardiogenic mesoderm), smooth muscle alpha-actin was expressed without the addition of BMP4. Interestingly, in cultured stage 6 posterolateral mesoderm, BMP2 induced the expressions of sarcomeric alpha-actinin and titin, but not of sarcomeric myosin. These results suggest that (1) BMP4 function lies upstream of the initial formation of I-Z-I components and A-bands separately in a stage-dependent manner, and (2) at least two signaling pathways are involved in the initial cardiac myofibrillogenesis: one is an unknown pathway responsible for the expression of smooth muscle alpha-actin; the other is BMP signaling, which is involved in the expression of sarcomeric alpha-actinin, titin, and sarcomeric myosin.

Animals↗

PubMed2002

BMP signaling is required for development of the ciliary body.

The ciliary body in the eye secretes aqueous humor and glycoproteins of the vitreous body and maintains the intraocular pressure. The ciliary muscle controls the shape of the lens through the ciliary zonules to focus the image onto the retina. During embryonic development, the ciliary epithelium is derived from the optic vesicle, but the molecular signals that control morphogenesis of the ciliary body are unknown. We report that lens-specific expression of a transgenic protein, Noggin, can block BMP signaling in the mouse eye and result in failure in formation of the ciliary processes. Co-expression of transgenic BMP7 restores normal development of the ciliary epithelium. Ectopic expression of Noggin also promotes differentiation of retinal ganglion cells. These results indicate that BMP signaling is required for development of the ciliary body and may also play a role in regulation of neuronal differentiation in the developing eye.

Animals↗

PubMed2001

Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding.

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.

Animals↗

PubMed2001

Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments.

Little is known about the genesis and patterning of tendons and other connective tissues, mostly owing to the absence of early markers. We have found that Scleraxis, a bHLH transcription factor, is a highly specific marker for all the connective tissues that mediate attachment of muscle to bone in chick and mouse, including the limb tendons, and show that early scleraxis expression marks the progenitor cell populations for these tissues. In the early limb bud, the tendon progenitor population is found in the superficial proximomedial mesenchyme. Using the scleraxis gene as a marker we show that these progenitors are induced by ectodermal signals and restricted by bone morphogenetic protein (BMP) signaling within the mesenchyme. Application of Noggin protein antagonizes this endogenous BMP activity and induces ectopic scleraxis expression. However, the presence of excess tendon progenitors does not lead to the production of additional or longer tendons, indicating that additional signals are required for the final formation of a tendon. Finally, we show that the endogenous expression of noggin within the condensing digit cartilage contributes to the induction of distal tendons.

Animals↗

PubMed2006

BMP is an important regulator of proepicardial identity in the chick embryo.

The proepicardium (PE) is a transient structure formed by pericardial coelomic mesothelium at the venous pole of the embryonic heart and gives rise to several cell types of the mature heart. In order to study PE development in chick embryos, we have analyzed the expression pattern of the marker genes Tbx18, Wt1, and Cfc. During PE induction, the three marker genes displayed a left-right asymmetric expression pattern. In each case, expression on the right side was stronger than on the left side. The left-right asymmetric gene expression observed here is in accord with the asymmetric formation of the proepicardium in the chick embryo. While initially the marker genes were expressed in the primitive sinus horn, subsequently, expression became confined to the PE mesothelium. In order to search for signaling factors involved in PE development, we studied Bmp2 and Bmp4 expression. Bmp2 was bilaterally expressed in the sinus venosus. In contrast, Bmp4 expression was initially expressed unilaterally in the right sinus horn and subsequently in the PE. In order to assess its functional role, BMP signaling was experimentally modulated by supplying exogenous BMP2 and by inhibiting endogenous BMP signaling through the addition of Noggin. Both supplying BMP and blocking BMP signaling resulted in a loss of PE marker gene expression. Surprisingly, both experimental situations lead to cardiac myocyte formation in the PE cultures. Careful titration experiments with exogenously added BMP2 or Noggin revealed that PE-specific marker gene expression depends on a low level of BMP signaling. Implantation of BMP2-secreting cells or beads filled with Noggin protein into the right sinus horn of HH stage 11 embryos resulted in downregulation of Tbx18 expression, corresponding to the results of the explant assay. Thus, a distinct level of BMP signaling is required for PE formation in the chick embryo.

Animals↗

PubMed2002

BMP pathways are involved in otic capsule formation and epithelial-mesenchymal signaling in the developing chicken inner ear.

The vertebrate inner ear consists of a complex labyrinth of epithelial cells that is surrounded by a bony capsule. The molecular mechanisms coordinating the development of the membranous and bony labyrinths are largely unknown. Previously, using avian retrovirus encoding Noggin (RCAS-Noggin) or beads soaked with Noggin protein, we have shown that bone morphogenetic proteins (BMPs) are important for the development of the otic epithelium in the chicken inner ear. Here, using two additional recombinant avian retroviruses, dominant negative and constitutively active forms of BMP receptors IB (BMPRIB), we show that BMPs, possibly acting through BMPRIB, are important for otic capsule formation. We also show that Bmp2 is strongly expressed in the prospective semicircular canals starting from the canal outpouch stage, suggesting that BMP2 plays an important role in canal formation. In addition, by correlating expression patterns of Bmps, their receptors, and localization of phosphorylated R-Smad (phospho R-Smad) immunoreactivity, an indicator of BMP activation, we show that BMPs emanating from the otic epithelium influence chondrogenesis of the otic capsule including the cartilage surrounding the semicircular canals.

Animals↗

PubMed1997

A role for bone morphogenetic proteins in the induction of cardiac myogenesis.

Little is known about the molecular mechanisms that govern heart specification in vertebrates. Here we demonstrate that bone morphogenetic protein (BMP) signaling plays a central role in the induction of cardiac myogenesis in the chick embryo. At the time when chick precardiac cells become committed to the cardiac muscle lineage, they are in contact with tissues expressing BMP-2, BMP-4, and BMP-7. Application of BMP-2-soaked beads in vivo elicits ectopic expression of the cardiac transcription factors CNkx-2.5 and GATA-4. Furthermore, administration of soluble BMP-2 or BMP-4 to explant cultures induces full cardiac differentiation in stage 5 to 7 anterior medial mesoderm, a tissue that is normally not cardiogenic. The competence to undergo cardiogenesis in response to BMPs is restricted to mesoderm located in the anterior regions of gastrula- to neurula-stage embryos. The secreted protein noggin, which binds to BMPs and antagonizes BMP activity, completely inhibits differentiation of the precardiac mesoderm, indicating that BMP activity is required for myocardial differentiation in this tissue. Together, these data imply that a cardiogenic field exists in the anterior mesoderm and that localized expression of BMPs selects which cells within this field enter the cardiac myocyte lineage.

Animals↗