@phdthesis{Rudolf2013,
  author    = {Rudolf, Ronald},
  title     = {Transcriptional Regulation of and by NFATc1 in Lymphocytes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-83993},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {The transcription factor NFATc1 has been shown to regulate the activation and differentiation of T-cells and B-cells, of DCs and megakaryocytes. Dysregulation of NFAT signaling was shown to be associated with the generation of autoimmune diseases, malignant transformation and the development of cancer [71]. The primary goal of this work was to gain insights on Nfatc1 induction and regulation in lymphocytes and to find new direct NFATc1 target genes. Three new BAC -transgenic reporter mouse strains (tgNfatc1/Egfp, tgNfatc1/DE1 and tgNfatc1/DE2) were applied to analyze Nfatc1 induction and regulation in primary murine B- and T-cells. As a result, we were able to show the persistent requirement of immunoreceptor-signaling for constant Nfatc1 induction, particularly, for NFATc1/αA expression. Furthermore, we showed that NF-κB inducing agents, such as LPS, CpG or CD40 receptor engagement, in combination with primary receptor-signals, positively contributed to Nfact1 induction in B-cells [137]. We sought to establish a new system which could help to identify direct NFATc1 target genes by means of ChIP and NGS in genom-wide approaches. We were able to successfully generate a new BAC-transgene encoding a biotinylatable short isoform of NFATc1, which is currently injected into mice oocyte at the TFM in Mainz. In addition, in vivo biotinylatable NFATc1-isoforms were cloned and stably expressed in the murine B-cell lymphoma line WEHI-231. The successful use of these cells stably overexpressing either the short NFATc1/αA or the long NFATc1/βC isoform along with the bacterial BirA biotin ligase was confirmed by intracellular stainings, FACS analysis, confocal microscopy and protein IP. By NGS, we detected 2185 genes which are specifically controlled by NFATc1/αA, and 1306 genes which are exclusively controlled by NFATc1/βC. This shows that the Nfatc1 locus encodes "two genes" which exhibit alternate, in part opposite functions. Studies on the induction of apoptosis and cell-death revealed opposed roles for the highly inducible short isoform NFATc1/αA and the constantly expressed long isoform NFATc1/βC. These findings were confirmed by whole transcriptome-sequencing performed with cells overexpressing NFATc1/αA and NFATc1/βC. Several thousand genes were found to be significantly altered in their expression profile, preferentially genes involved in apoptosis and PCD for NFATc1/βC or genes involved in transcriptional regulation and cell-cycle processes for NFATc1/αA. In addition we were able to perform ChIP-seq for NFATc1/αA and NFATc1/βC in an ab-independent approach. We found potential new target-sites, but further studies will have to address this ambitious goal in the future. In individual ChIP assays, we showed direct binding of NFATc1/αA and NFATc1/βC to the Prdm1 and Aicda promoter regions which are individually controlled by the NFATc1 isoforms.},
  subject      = {Lymphozyt},
  language  = {en}
}
@article{MuellerFiebigWeidaueretal.2013,
  author    = {Mueller, Thomas D. and Fiebig, Juliane E. and Weidauer, Stella E. and Qiu, Li-Yan and Bauer, Markus and Schmieder, Peter and Beerbaum, Monika and Zhang, Jin-Li and Oschkinat, Hartmut and Sebald, Walter},
  title     = {The Clip-Segment of the von Willebrand Domain 1 of the BMP Modulator Protein Crossveinless 2 Is Preformed},
  series = {Molecules},
  journal   = {Molecules},
  doi       = {10.3390/molecules181011658},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97196},
  year      = {2013},
  abstract  = {Bone Morphogenetic Proteins (BMPs) are secreted protein hormones that act as morphogens and exert essential roles during embryonic development of tissues and organs. Signaling by BMPs occurs via hetero-oligomerization of two types of serine/threonine kinase transmembrane receptors. Due to the small number of available receptors for a large number of BMP ligands ligand-receptor promiscuity presents an evident problem requiring additional regulatory mechanisms for ligand-specific signaling. Such additional regulation is achieved through a plethora of extracellular antagonists, among them members of the Chordin superfamily, that modulate BMP signaling activity by binding. The key-element in Chordin-related antagonists for interacting with BMPs is the von Willebrand type C (VWC) module, which is a small domain of about 50 to 60 residues occurring in many different proteins. Although a structure of the VWC domain of the Chordin-member Crossveinless 2 (CV2) bound to BMP-2 has been determined by X-ray crystallography, the molecular mechanism by which the VWC domain binds BMPs has remained unclear. Here we present the NMR structure of the Danio rerio CV2 VWC1 domain in its unbound state showing that the key features for high affinity binding to BMP-2 is a pre-oriented peptide loop.},
  language  = {en}
}
@article{StotzMuellerZoelleretal.2013,
  author    = {Stotz, Henrik U. and Mueller, Stefan and Zoeller, Maria and Mueller, Martin J. and Berger, Susanne},
  title     = {TGA transcription factors and jasmonate-independent COI1 signalling regulate specific plant responses to reactive oxylipins},
  series = {Journal of Experimental Botany},
  volume    = {64},
  journal   = {Journal of Experimental Botany},
  number    = {4},
  doi       = {10.1093/jxb/ers389},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132318},
  pages     = {963-975},
  year      = {2013},
  abstract  = {Jasmonates and phytoprostanes are oxylipins that regulate stress responses and diverse physiological and developmental processes. 12-Oxo-phytodienoic acid (OPDA) and phytoprostanes are structurally related electrophilic cyclopentenones, which activate similar gene expression profiles that are for the most part different from the action of the cyclopentanone jasmonic acid (JA) and its biologically active amino acid conjugates. Whereas JA-isoleucine signals through binding to COI1, the bZIP transcription factors TGA2, TGA5, and TGA6 are involved in regulation of gene expression in response to phytoprostanes. Here root growth inhibition and target gene expression were compared after treatment with JA, OPDA, or phytoprostanes in mutants of the COI1/MYC2 pathway and in different TGA factor mutants. Inhibition of root growth by phytoprostanes was dependent on COI1 but independent of jasmonate biosynthesis. In contrast, phytoprostane-responsive gene expression was strongly dependent on TGA2, TGA5, and TGA6, but not dependent on COI1, MYC2, TGA1, and TGA4. Different mutant and overexpressing lines were used to determine individual contributions of TGA factors to cyclopentenone-responsive gene expression. Whereas OPDA-induced expression of the cytochrome P450 gene CYP81D11 was primarily regulated by TGA2 and TGA5, the glutathione S-transferase gene GST25 and the OPDA reductase gene OPR1 were regulated by TGA5 and TGA6, but less so by TGA2. These results support the model that phytoprostanes and OPDA regulate differently (i) growth responses, which are COI1 dependent but jasmonate independent; and (ii) lipid stress responses, which are strongly dependent on TGA2, TGA5, and TGA6. Identification of molecular components in cyclopentenone signalling provides an insight into novel oxylipin signal transduction pathways.},
  language  = {en}
}
@phdthesis{Kamke2013,
  author    = {Kamke, Janine},
  title     = {Single-cell genomics of the candidate phylum Poribacteria},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85042},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Marine sponges are the most ancient metazoans and of large ecological importance as drivers of water and nutrient flows in benthic habitats. Furthermore marine sponges are well known for their association with highly abundant and diverse microbial consortia. Microorganisms inhabit the extracellular matrix of marine sponges where they can make up to 35\% of the sponge's biomass. Many microbial symbionts of marine sponges are highly host specific and cannot, or only in very rare abundances, be found outside of their host environment. Of special interest is the candidate phylum Poribacteria that was first discovered in marine sponges and still remains almost exclusive to their hosts. Phylogenetically Poribacteria were placed into the Planctomycetes, Verrucomicrobia, Chlamydiae superphylum and similarly to many members of this superphylum cell compartmentation has been proposed to occur in members of the Poribacteria. The status as a candidate phylum implies that no member of Poribacteria has been obtained in culture yet. This restricts the investigations of Poribacteria and their interactions with marine sponges to culture independent methods and makes functional characterisation a difficult task. In this PhD thesis I used the novel method of single-cell genomics to investigate the genomic potential of the candidate phylum Poribacteria. Single-cell genomics enables whole genome sequencing of uncultivated microorganisms by singularising cells from the environment, subsequent cell lysis and multiple displacement amplification of the total genomic DNA. This process yields sufficient amounts of DNA for whole genome sequencing and genome analysis. This technique and its relevance for symbiosis studies are discussed in this PhD thesis. Through the application of single-cell genomics it was possible to increase the number of single-amplified genomes of the candidate phylum Poribacteria from initially one to a total of six. Analyses of these datasets made it possible to enhance our understanding of the metabolism, taxonomy, and phylum diversity of Poribacteria and thus made these one of the best-characterised sponge symbionts today. The poribacterial genomes represented three phylotypes within the candidate phylum of which one appeared dominant. Phylogenetic and phylogenomic analyses revealed a novel phylogenetic positioning of Poribacteria distinctly outside of the Planctomycete, Verrucomicorbia, Chlamydiae superphylum. The occurrence of cell compartmentation in Poribacteria was also revisited based on the obtained genome sequences and revealed evidence for bacterial microcompartments instead of the previously suggested nucleotide-like structures. An extensive genomic repertoire of glycoside hydrolases, glycotransferases, and other carbohydrate active enzymes was found to be the central shared feature between all poribacterial genomes and showed that Poribacteria are among those marine bacteria with the largest genomic repertoire for carbohydrate degradation. Detailed analysis of the carbohydrate metabolism revealed that Poribacteria have the genomic potential for degradation of a variety of polymers, di- and monosaccharaides that allow these symbionts to feed various nutrient sources accessible through the filter-feeding activities of the sponge host. Furthermore the poribacterial glycobiome appeared to enable degradation of glycosaminoglycan chains, one of the main building blocks of extracellular matrix of marine sponges. Different lifestyles resulting from the poribacterial carbohydrate degradation potential are discussed including the influence of nutrient cycling in sponges, nutrient recycling and scavenging. The findings of this thesis emphasise the long overlooked importance of heterotrophic symbionts such as Poribacteria for the interactions with marine sponges and represent a solid basis for future studies of the influence heterotrophic symbionts have on their sponge hosts.},
  subject      = {Bakterien},
  language  = {en}
}
@phdthesis{Niemann2013,
  author    = {Niemann, Sylvia},
  title     = {Seed Coat Permeability of Active Ingredients},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-79585},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {The seed coat is the barrier controlling exchange of solutes between the plant embryo and its environment. This exchange is of importance for example in the uptake of germination inhibitors or in the uptake of agrochemicals applied as seed treatment. A thorough understanding of the basic mechanisms underlying solute permeation across the seed coat would help to improve the effectiveness of seed treatment formulations. In seed treatment formulations, additives can be used to enhance or decrease mobility or uptake of the active ingredient (AI). In the present study the seed coat barrier properties and the seed coat permeation process was examined with the model species Pisum sativum and with a set of model solutes. The lipophilic fraction of the seed coat was analysed by gas chromatography and mass spectrometry and it was found that the total lipophilic compartment of the seed coat represents 0.61 \% of the weight of a swollen seed coat. The seed is covered by a lipophilic cuticle. The seed coat coverage with cuticular waxes is ten to 18-fold lower than wax coverage of pea leaves, though. In order to examine sorption of solutes in the small lipophilic compartment of the seed coat, seed coat/water partition coefficients were determined. These cover a much smaller range than the corresponding n-octanol/water partition coefficients. The lipophilic sorption compartment as calculated from the seed coat/water partition coefficient data is smaller than the analysed total lipophilic compartment of the seed coat since not all of the lipid components can act as sorption compartment. During seed swelling, the pea seed nearly doubles its weight. The uptake of water is driven by the very low water potential of the dry seed and controlled by the seed coat hydraulic conductivity both of which increase during seed swelling. Depending on the available form of water, water uptake can take place by diffusion from air humidity or by mass flow from liquid water. Water uptake by a seed in moist sand takes place by a combination of both uptake mechanisms. The basic transport mechanism underlying solute permeation of seed coats was analysed by steady-state experiments with a newly devised experimental setup. The permeance P for permeation of the set of model compounds across isolated seed coat halves ranged from 3.34 x 10-8 m s-1 for abamectin to 18.9 x 10-8 m s-1 for caffeine. It was found that solute permeation across the seed coat takes aqueous pathways. This was concluded from the facts that molar volume instead of lipophilicity of the solutes determine permeation and that the temperature effect on permeation is very small. This is in contrast to typical leaf and fruit cuticular uptake where lipophilic pathways dominate. Solute uptake across the seed coat can take place by two different mechanisms both of which take aqueous pathways. Uptake can be by diffusion and in the presence of a bulk flow of water driven by a water potential difference also by solvent drag. The presence of the solvent drag uptake mechanism shows that the aqueous pathways form an aqueous continuum across the seed coat. These findings indicate that the seed coat covering cuticle does not form a continuous barrier enclosing the seed. In order to examine solute uptake across the seed coat under conditions close to a situation taking place in the field, the process of uptake of a seed treatment AI in the field was simulated. In the situation of a treated seed in the field, the seed treatment residue dissolves and then the AI can move either into the surrounding soil or across the seed coat into the seed. Uptake across the seed coat can take place either by diffusion or during seed swelling by the solvent drag mechanism. Since the seed treatment residue depletes over time, non-steady-state uptake takes place. To simulate these processes, laboratory scale seed treatment methods were established to produce treated seeds and isolated treated seed coat halves. Experimental setups for non-steady-state uptake experiments were established with whole treated seeds and with isolated treated seed coat halves as simplified screening tool. By modelling of the AI uptake as a first-order process the rate constant k and the final relative uptake amount Mt→∞ M0-1 were obtained. With k and Mt→∞ M0-1 a quantification and comparison of the uptake curves was possible. Both in the experiments with whole treated seeds and with isolated treated seed coats, uptake of metalaxyl-M was much faster than uptake of sedaxane. In the uptake of a seed treatment AI, not only the solute's molar volume but also its water solubility determine uptake. The solute's water solubility is important for dissolution of the AI from the seed treatment residue and thus determines availability of the AI for uptake. Water solubility also controls the possible concentration in solution and thus the driving force for diffusive uptake. Furthermore, the AI amount taken up by solvent drag is determined by concentration in the inflowing water and thus by water solubility. In the experiments with whole treated seeds the additive effects on uptake were smaller than in the experiments with isolated treated seed coats or not significant. Adigor functions as an emulsifier and can lead to a slight increase of AI mobilisation from the seed treatment residue. NeoCryl A-2099 can cause a slowed down release of the AI from the seed treatment residue. The effects of both additives were smaller than the effect caused by different AI physico-chemical properties. Therefore, the most important factor determining uptake of a seed treatment AI are the AI's physico-chemical properties, especially its water solubility.},
  subject      = {Samenschale},
  language  = {en}
}
@article{WallerMuellerPedrotti2013,
  author    = {Waller, Frank and Mueller, Martin J. and Pedrotti, Lorenzo},
  title     = {Piriformospora indica Root Colonization Triggers Local and Systemic Root Responses and Inhibits Secondary Colonization of Distal Roots},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  doi       = {10.1371/journal.pone.0069352},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96493},
  year      = {2013},
  abstract  = {Piriformospora indica is a basidiomycete fungus colonizing roots of a wide range of higher plants, including crop plants and the model plant Arabidopsis thaliana. Previous studies have shown that P. indica improves growth, and enhances systemic pathogen resistance in leaves of host plants. To investigate systemic effects within the root system, we established a hydroponic split-root cultivation system for Arabidopsis. Using quantitative real-time PCR, we show that initial P. indica colonization triggers a local, transient response of several defense-related transcripts, of which some were also induced in shoots and in distal, non-colonized roots of the same plant. Systemic effects on distal roots included the inhibition of secondary P. indica colonization. Faster and stronger induction of defense-related transcripts during secondary inoculation revealed that a P. indica pretreatment triggers root-wide priming of defense responses, which could cause the observed reduction of secondary colonization levels. Secondary P. indica colonization also induced defense responses in distant, already colonized parts of the root. Endophytic fungi therefore trigger a spatially specific response in directly colonized and in systemic root tissues of host plants.},
  language  = {en}
}
@phdthesis{Chintalapati2013,
  author    = {Chintalapati, Chakravarthi},
  title     = {Ornithine decarboxylase is the receptor of regulatory protein RS1 (RSC1A1) mediating RS1 dependent shortterm regulation of glucose transporter SGLT1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85622},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {RS1 is the intron less singel copy gene involved in regulation of plasme membrane transporters. Ornithine decarboxylase is identified as the receptor of RS1 specific for the release of vesicles containing SGLT1 specifically at the trans-golgi network. RS1 decreases the activity of ODC there by inhibiting the release of vesicles containing specifically SGLT1.},
  subject      = {Ornithindecarboxylase},
  language  = {en}
}
@phdthesis{Solanki2013,
  author    = {Solanki, Narendra},
  title     = {Novelty choice in Drosophila melanogaster},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-103219},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {This study explores novelty choice, a behavioral paradigm for the investigation of visual pattern recognition and learning of the fly Drosophila melanogaster in the flight simulator. Pattern recognition in novelty choice differs significantly from pattern recognition studied by heat conditioning, although both paradigms use the same test. Out of the four pattern parameters that the flies can learn in heat conditioning, novelty choice can be shown for height (horizontal bars differing in height), size and vertical compactness but not for oblique bars oriented at +/- 45°. Upright and inverted Ts [differing in their centers of gravity (CsOG) by 13°] that have been extensively used for heat conditioning experiments, do not elicit novelty choice. In contrast, horizontal bars differing in their CsOG by 13° do elicit novelty choice; so do the Ts after increasing their CsOG difference from 13° to 23°. This indicates that in the Ts the heights of the CsOG are not the only pattern parameters that matter for the novelty choice behavior. The novelty choice and heat conditioning paradigms are further differentiated using the gene rutabaga (rut) coding for a type 1 adenylyl cyclase. This protein had been shown to be involved in memory formation in the heat conditioning paradigm. Novelty choice is not affected by mutations in the rut gene. This is in line with the finding that dopamine, which in olfactory learning is known to regulate Rutabaga via the dopamine receptor Dumb in the mushroom bodies, is dispensable for novelty choice. It is concluded that in novelty choice the Rut cAMP pathway is not involved. Novelty choice requires short term working memory, as has been described in spatial orientation during locomotion. The protein S6KII that has been shown to be involved in visual orientation memory in walking flies is found here to be also required for novelty choice. As in heat conditioning the central complex plays a major role in novelty choice. The S6KII mutant phenotype for height can be rescued in some subsets of the ring neurons of the ellipsoid body. In addition the finding that the ellipsoid body mutants ebo678 and eboKS263 also show a mutant phenotype for height confirm the importance of ellipsoid body for height novelty choice. Interestingly some neurons in the F1 layer of the fan-shaped body are necessary for height novelty choice. Furthermore, different novelty choice phenotypes for different pattern parameters are found with and without mushroom bodies. Mushroom bodies are required in novelty choice for size but they are dispensable for height and vertical compactness. This special circuit requirement for the size parameter in novelty choice is found using various means of interference with mushroom body function during development or adulthood.},
  subject      = {Taufliege},
  language  = {en}
}
@phdthesis{Solanki2013,
  author    = {Solanki, Narendra},
  title     = {Novelty choice in Drosophila melanogaster},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-78377},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {This study explores novelty choice, a behavioral paradigm for the investigation of visual pattern recognition and learning of the fly Drosophila melanogaster in the flight simulator. Pattern recognition in novelty choice differs significantly from pattern recognition studied by heat conditioning, although both paradigms use the same test. Out of the four pattern parameters that the flies can learn in heat conditioning, novelty choice can be shown for height (horizontal bars differing in height), size and vertical compactness but not for oblique bars oriented at +/- 45°. Upright and inverted Ts [differing in their centers of gravity (CsOG) by 13°] that have been extensively used for heat conditioning experiments, do not elicit novelty choice. In contrast, horizontal bars differing in their CsOG by 13° do elicit novelty choice; so do the Ts after increasing their CsOG difference from 13° to 23°. This indicates that in the Ts the heights of the CsOG are not the only pattern parameters that matter for the novelty choice behavior. The novelty choice and heat conditioning paradigms are further differentiated using the gene rutabaga (rut) coding for a type 1 adenylyl cyclase. This protein had been shown to be involved in memory formation in the heat conditioning paradigm. Novelty choice is not affected by mutations in the rut gene. This is in line with the finding that dopamine, which in olfactory learning is known to regulate Rutabaga via the dopamine receptor Dumb in the mushroom bodies, is dispensable for novelty choice. It is concluded that in novelty choice the Rut cAMP pathway is not involved. Novelty choice requires short term working memory, as has been described in spatial orientation during locomotion. The protein S6KII that has been shown to be involved in visual orientation memory in walking flies is found here to be also required for novelty choice. As in heat conditioning the central complex plays a major role in novelty choice. The S6KII mutant phenotype for height can be rescued in some subsets of the ring neurons of the ellipsoid body. In addition the finding that the ellipsoid body mutants ebo678 and eboKS263 also show a mutant phenotype for height confirm the importance of ellipsoid body for height novelty choice. Interestingly some neurons in the F1 layer of the fan-shaped body are necessary for height novelty choice. Furthermore, different novelty choice phenotypes for different pattern parameters are found with and without mushroom bodies. Mushroom bodies are required in novelty choice for size but they are dispensable for height and vertical compactness. This special circuit requirement for the size parameter in novelty choice is found using various means of interference with mushroom body function during development or adulthood.},
  subject      = {Drosophila melanogaster},
  language  = {en}
}
@article{BoschertvanDintherWeidaueretal.2013,
  author    = {Boschert, Verena and van Dinther, Maarten and Weidauer, Stella and van Pee, Katharina and Muth, Eva-Maria and ten Dijke, Peter and Mueller, Thomas D.},
  title     = {Mutational Analysis of Sclerostin Shows Importance of the Flexible Loop and the Cystine-Knot for Wnt-Signaling Inhibition},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {11},
  doi       = {10.1371/journal.pone.0081710},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129862},
  pages     = {e81710},
  year      = {2013},
  abstract  = {The cystine-knot containing protein Sclerostin is an important negative regulator of bone growth and therefore represents a promising therapeutic target. It exerts its biological task by inhibiting the Wnt (wingless and int1) signaling pathway, which participates in bone formation by promoting the differentiation of mesenchymal stem cells to osteoblasts. The core structure of Sclerostin consists of three loops with the first and third loop (Finger 1 and Finger 2) forming a structured \(\beta\)-sheet and the second loop being unstructured and highly flexible. Biochemical data showed that the flexible loop is important for binding of Sclerostin to Wnt co-receptors of the low-density lipoprotein related-protein family (LRP), by interacting with the Wnt co-receptors LRP5 or -6 it inhibits Wnt signaling. To further examine the structural requirements for Wnt inhibition, we performed an extensive mutational study within all three loops of the Sclerostin core domain involving single and multiple mutations as well as truncation of important regions. By this approach we could confirm the importance of the second loop and especially of amino acids Asn92 and Ile94 for binding to LRP6. Based on a Sclerostin variant found in a Turkish family suffering from Sclerosteosis we generated a Sclerostin mutant with cysteines 84 and 142 exchanged thereby removing the third disulfide bond of the cystine-knot. This mutant binds to LRP6 with reduced binding affinity and also exhibits a strongly reduced inhibitory activity against Wnt1 thereby showing that also elements outside the flexible loop are important for inhibition of Wnt by Sclerostin. Additionally, we examined the effect of the mutations on the inhibition of two different Wnt proteins, Wnt3a and Wnt1. We could detect clear differences in the inhibition of these proteins, suggesting that the mechanism by which Sclerostin antagonizes Wnt1 and Wnt3a is fundamentally different.},
  language  = {en}
}