Interaction of Ihh and BMP/Noggin Signaling during Cartilage Differentiation

AbstractBone morphogenetic proteins (BMPs) have been implicated in regulating multiple stages of bone development. Recently it has been shown that constitutive activation of theBMP receptor-IAblocks chondrocyte differentiation in a similar manner as misexpression ofIndian hedgehog.In this paper we analyze the role of BMPs as possible mediators of Indian hedgehog signaling and useNogginmisexpression to gain insight into additional roles of BMPs during cartilage differentiation. We show by comparative analysis ofBMPandIhhexpression domains that the borders ofIndian hedgehogexpression in the chondrocytes are reflected in changes of the expression level of severalBMPgenes in the adjacent perichondrium. We further demonstrate that misexpression ofIndian hedgehogappears to directly upregulateBMP2andBMP4expression, independent of the differentiation state of the flanking chondrocytes. In contrast, changes inBMP5andBMP7expression in the perichondrium correspond to altered differentiation states of the flanking chondrocytes. In addition,NogginandChordin,which are both expressed in the developing cartilage elements, also change their expression pattern afterIhhmisexpression. Finally, we use retroviral misexpression ofNoggin,a potent antagonist of BMP signaling, to gain insight into additional roles of BMP signaling during cartilage differentiation. We find that BMP signaling is necessary for the growth and differentiation of the cartilage elements. In addition, this analysis revealed that the members of the BMP/Noggin signaling pathway are linked in a complex autoregulatory network

Multiple attractors and long transients in spatially structured populations with an Allee effect

We present a discrete-time model of a spatially structured population and explore the effects of coupling when the local dynamics contain a strong Allee effect and overcompensation. While an isolated population can exhibit only bistability and essential extinction, a spatially structured population can exhibit numerous coexisting attractors. We identify mechanisms and parameter ranges that can protect the spatially structured population from essential extinction, whereas it is inevitable in the local system. In the case of weak coupling, a state where one subpopulation density lies above and the other one below the Allee threshold can prevent essential extinction. Strong coupling, on the other hand, enables both populations to persist above the Allee threshold when dynamics are (approximately) out-of-phase. In both cases, attractors have fractal basin boundaries. Outside of these parameter ranges, dispersal was not found to prevent essential extinction. We also demonstrate how spatial structure can lead to long transients of persistence before the population goes extinct.Comment: 25 pages, 9 figures, Submitted to Bulletin of Mathematical Biolog

BMP signaling balances proliferation and differentiation of muscle satellite cell descendants

<p>Abstract</p> <p>Background</p> <p>The capacity of muscle to grow or to regenerate after damage is provided by adult stem cells, so called satellite cells, which are located under the basement lamina of each myofiber. Upon activation satellite cells enter the cell cycle, proliferate and differentiate into myoblasts, which fuse to injured myofibers or form new fibers. These processes are tightly controlled by many growth factors.</p> <p>Results</p> <p>Here we investigate the role of bone morphogenetic proteins (BMPs) during satellite cell differentiation. Unlike the myogenic C2C12 cell line, primary satellite cells do not differentiate into osteoblasts upon BMP signaling. Instead BMP signaling inhibits myogenic differentiation of primary satellite cells <it>ex vivo</it>. In contrast, inhibition of BMP signaling results in cell cycle exit, followed by enhanced myoblast differentiation and myotube formation. Using an <it>in vivo </it>trauma model we demonstrate that satellite cells respond to BMP signals during the regeneration process. Interestingly, we found the BMP inhibitor <it>Chordin </it>upregulated in primary satellite cell cultures and in regenerating muscles. In both systems <it>Chordin </it>expression follows that of Myogenin, a marker for cells committed to differentiation.</p> <p>Conclusion</p> <p>Our data indicate that BMP signaling plays a critical role in balancing proliferation and differentiation of activated satellite cells and their descendants. Initially, BMP signals maintain satellite cells descendants in a proliferating state thereby expanding cell numbers. After cells are committed to differentiate they upregulate the expression of the BMP inhibitor <it>Chordin </it>thereby supporting terminal differentiation and myotube formation in a negative feedback mechanism.</p

Four-jointed knock-out delays renal failure in an ADPKD model with kidney injury

Autosomal Dominant Polycystic Kidney Disease is characterised by the development of fluid-filled cysts in the kidneys which lead to end-stage renal disease (ESRD). In the majority of cases, the disease is caused by a mutation in the Pkd1 gene. In a previous study, we demonstrated that renal injury can accelerate cyst formation in Pkd1 knock-out (KO) mice. In that study, we found that after injury four-jointed (Fjx1), an upstream regulator of planar cell polarity and the Hippo pathway, was aberrantly expressed in Pkd1 KO mice compared to WT. Therefore, we hypothesised a role for Fjx1 in injury/repair and cyst formation. We generated single and double deletion mice for Pkd1 and Fjx1, and we induced toxic renal injury using the nephrotoxic compound 1,2-dichlorovinyl-cysteine. We confirmed that nephrotoxic injury can accelerate cyst formation in Pkd1 mutant mice. This caused Pkd1 KO mice to reach ESRD significantly faster; unexpectedly, double KO mice survived significantly longer. Cyst formation was comparable in both models, but we found significantly less fibrosis and macrophage infiltration in double KO mice. Taken together, these data suggest that Fjx1 disruption protects the cystic kidneys against kidney failure by reducing inflammation and fibrosis. Moreover, we describe, for the first time, an interesting (yet unidentified) mechanism that partially discriminates cyst growth from fibrogenesis. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Konjunkturen der NS-Bewegung: eine Untersuchung der Veranstaltungsaktivitäten der Münchener NSDAP, 1925-1930

"Basierend auf den Erkenntnissen der Soziologie sozialer Bewegungen werden die unterschiedlichen Konjunkturen in der Konstitutionsphase der NSDAP in München von 1925 bis 193O untersucht. Insbesondere wird entlang von framing-Strategien der Frage nachgegangen, ob und in welchem Maß die Nutzung besonderer Opportunitätsstrukturen der Partei den Durchbruch bei den Reichstagswahlen im September 1930 ermöglicht hat. Mittels einer inhaltsanalytischen Auswertung der im Völkischen Beobachter angekündigten Vortragsthemen öffentlicher Veranstaltungen der NSDAP in München kann gezeigt werden, daß es der NSDAP in dem ausgeprägten konjunkturellen 'auf und ab' der Parteiaktivitäten seit Anfang 1929 gelungen ist, dank eines zusammenhängenden Rahmens von Themen und deren geschickter Einbindung in identity, injustice und agency frames, spezifische political opportunities in geeigneter Weise in Sinnmuster zu integrieren und als zentrale Probleme für den Bewegungserfolg operativ und effektiv zu nutzen. Diese framing-Leistung ist der NSDAP in ihrer Durchbruchsphase offensichtlich mit eindrucksvollem Erfolg gelungen und hat ihren Aufstieg zur Macht zumindest erleichtert." (Autorenreferat)"Following insights of social movement theory, this paper looks at movement cycles during the initial development of the NSDAP in Munich between 1925 and 1930. The paper explores the different framing strategies the party employed in trying to make efficient use of opportunity structures in the political discourse of the late 1920s, for the mobilizations of resources and popular support. It is argued that changes in framing strategies after 1928 provided an important ingredient leading to the party's political breakthrough with the national elections of September 1930. Based on a content analysis of the official party newspaper, Völkischer Beobachter, the topics of political events and speeches the NSDAP organized in Munich between 1925 and 1930 are analyzed. The results show that, after a period of political difficulties in 1927-1928, the NSDAP managed to achieve a coherent set of themes around economic and political issues that had been characteristically absent in previous periods. Specifically, evidence is found that from 1929 onwards, the party managed to integrate an injustice frame with an identity frame and an agency frame to forge a politically powerful and forward-looking message that may have facilitated both its acceptance among broader segments of the population, and its ultimate rise to power." (author's abstract

Regulation of Calvarial Osteogenesis by Concomitant De-repression of GLI3 and Activation of IHH Targets

Loss-of-function mutations in GLI3 and IHH cause craniosynostois and reduced osteogeneiss, respectively. In this study, we show that ihh ligand, the receptor Ptch1 and Gli transcription factors are differentialyy expressed in embryonic mouse calvaria osteogenic condenstions. We show that in both ihh(-/-) and Gli3(Xt-J/Xt-J) embroyonic mice, the normal gene expression architecture is lost and this results in disorganized calvarial bone developement. RUNX2 is a master regulatory transciption factor controlling osteogenesis. In the absence of Gli3, RUNX2 isoform II and IHH are upregulated, and RUNX2 isoform I downregulated. This is consistent with the expandeed and aberant osteogenesis observed in Gli3Xt-J/Xt-J mice, and consistent RunX2-t expression by relatively immature osteoprogenitors. ihh-/- mice exhibited small calvarial bones HH target genes, Ptch1 and Gli1, were absent. This indicates that IHH is the functional HH ligand, and that it is not compensated by another HH ligand. To decipher the roles and potential interaction of Gli3 and ihh. we generated ihh-/-; gli3Xt-J/Xt-J compound mutant mice. Even in the absence of ihh, Gli3 deletion was sufficient to induce aberrant precocious ossification across the developing suture, indicating that the carniosyostosis pehnotype of Gli3Xt-J/Xt-J mice is not dependent on IHH ligand. Also we found that ihh was not required for Runx2 expression as the expression of RUNX2 target genes was unaffected by deletion of Ihh. To test whether RUNX2 has a role upstream of IHH we performed RUNX2 siRNA knock down experiements in WT calvarial osteoblasts and explants and found that Ihh expression is suppressed. Our results show that IHH is the functional HH ligand in the embroynic mouse calvaria osteogenic condensations, where it regulates the progression of osteoblastic differentation. As GLI3 represses the expression of Runx2-II abd Ihh, and also elevats the Runx2-I expression, and as IHH may be regulated by RUNX2 these results raise the possibility of a regualtory feedback circuit to control calvarial osteogenesis and suture patency. Taken together RUNX2-controlled osteoblastic cell fate is regulated by IHH through concomitant inhibition of GLI3-repressor formation and activation of downstreams targets.Peer reviewe

Ice Algae-Produced Carbon Is Critical for Overwintering of Antarctic Krill Euphausia superba

Antarctic krill Euphausia superba (“krill”) constitute a fundamental food source for Antarctic seabirds and mammals, and a globally important fisheries resource. The future resilience of krill to climate change depends critically on the winter survival of young krill. To survive periods of extremely low production by pelagic algae during winter, krill are assumed to rely partly on carbon produced by ice algae. The true dependency on ice algae-produced carbon, however, is so far unquantified. This confounds predictions on the future resilience of krill stocks to sea ice decline. Fatty acid (FA) analysis, bulk stable isotope analysis (BSIA), and compound-specific stable isotope analysis (CSIA) of diatom- and dinoflagellate-associated marker FAs were applied to quantify the dependency of overwintering larval, juvenile, and adult krill on ice algae-produced carbon (αIce) during winter 2013 in the Weddell-Scotia Confluence Zone. Our results demonstrate that the majority of the carbon uptake of the overwintering larval and juvenile krill originated from ice algae (up to 88% of the carbon budget), and that the dependency on ice algal carbon decreased with ontogeny, reaching <56% of the carbon budget in adults. Spatio-temporal variability in the utilization of ice algal carbon was more pronounced in larvae and juvenile krill than in adults. Differences between αIce estimates derived from short- vs. long-term FA-specific isotopic compositions suggested that ice algae-produced carbon gained importance as the winter progressed, and might become critical at the late winter-spring transition, before the phytoplankton bloom commences. Where the sea ice season shortens, reduced availability of ice algae might possibly not be compensated by surplus phytoplankton production during wintertime. Hence, sea ice decline could seriously endanger the winter survival of recruits, and subsequently overall biomass of krill

The chondro-osseous continuum: is it possible to unlock the potential assigned within?

Endochondral ossification (EO), by which long bones of the axial skeleton form, is a tightly regulated process involving chondrocyte maturation with successive stages of proliferation, maturation, and hypertrophy, accompanied by cartilage matrix synthesis, calcification, and angiogenesis, followed by osteoblast-mediated ossification. This developmental sequence reappears during fracture repair and in osteoarthritic etiopathology. These similarities suggest that EO, and the cells involved, are of great clinical importance for bone regeneration as it could provide novel targeted approaches to increase specific signaling to promote fracture healing, and if regulated appropriately in the treatment of osteoarthritis. The long-held accepted dogma states that hypertrophic chondrocytes are terminally differentiated and will eventually undergo apoptosis. In this mini review, we will explore recent evidence from experiments that revisit the idea that hypertrophic chondrocytes have pluripotent capacity and may instead transdifferentiate into a specific sub-population of osteoblast cells. There are multiple lines of evidence, including our own, showing that local, selective alterations in cartilage extracellular matrix (ECM) remodeling also indelibly alter bone quality. This would be consistent with the hypothesis that osteoblast behavior in long bones is regulated by a combination of their lineage origins and the epigenetic effects of chondrocyte-derived ECM which they encounter during their recruitment. Further exploration of these processes could help to unlock potential novel targets for bone repair and regeneration and in the treatment of osteoarthritis

The transcriptionally active bacterial communities of grapevine rhizosphere in dependence on rootstock and scion variety

The rhizosphere is where crucial processes for the productivity of viticultural systems occur. The composition of the bacterial communities associated with the rhizosphere of grapevines is known to depend on plant genotype. However, the genotype of grafted grapevines differs between scion and rootstock; the role of each genotype is unclear. To untangle the effect of scion and rootstock, the rRNA (V4–V5 region of 16S rRNA) extracted from the rhizosphere of the grape varieties Riesling and Mueller-Thurgau ungrafted vs grafted on different rootstocks was sequenced. The bioinformatic analysis with tools designed to be robust for compositional data showed that the investigated rootstocks or scions or combinations, respectively, recruited bacterial communities with distinguishable traits. Statistical differences were revealed between ungrafted Riesling vs Mueller-Thurgau, between grafted Riesling vs ungrafted Riesling, and between ungrafted Mueller-Thurgau vs grafted Mueller-Thurgau. Thus, confirming the role of scion and rootstock genotype as a driver of the structure and composition of bacterial communities in the rhizosphere of grapevines

The skeletal phenotype of chondroadherin deficient mice

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their a2b1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the a1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth