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Markus Bussen

Bio: Markus Bussen is an academic researcher from Hochschule Hannover. The author has contributed to research in topics: Paraxial mesoderm & Heart failure. The author has an hindex of 7, co-authored 8 publications receiving 2857 citations. Previous affiliations of Markus Bussen include University of California, San Francisco & Elsevier.

Papers
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Journal ArticleDOI
18 Dec 2008-Nature
TL;DR: It is shown that microRNA-21 regulates the ERK–MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function and confirms miR-21 as a disease target in heart failure and establishes the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.
Abstract: MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of microRNAs by several mechanisms has been described in various disease states including cardiac disease. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK-MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.

2,206 citations

Journal ArticleDOI
TL;DR: This paper found that the sinus horns formed only after heart looping by differentiation of mesenchymal cells of the septum transversum region into myocardium, and they did not derive from cells previously positive for Nkx2-5.
Abstract: The venous pole of the mammalian heart is a structurally and electrically complex region, yet the lineage and molecular mechanisms underlying its formation have remained largely unexplored. In contrast to classical studies that attribute the origin of the myocardial sinus horns to the embryonic venous pole, we find that the sinus horns form only after heart looping by differentiation of mesenchymal cells of the septum transversum region into myocardium. The myocardial sinus horns and their mesenchymal precursor cells never express Nkx2-5, a transcription factor critical for heart development. In addition, lineage studies show that the sinus horns do not derive from cells previously positive for Nkx2-5. In contrast, the sinus horns express the T-box transcription factor gene Tbx18. Mice deficient for Tbx18 fail to form sinus horns from the pericardial mesenchyme and have defective caval veins, whereas the pulmonary vein and atrial structures are unaffected. Our studies define a novel heart precursor population that contributes exclusively to the myocardium surrounding the sinus horns or systemic venous tributaries of the developing heart, which are a source of congenital malformation and cardiac arrhythmias.

255 citations

Journal ArticleDOI
TL;DR: It is demonstrated that maintenance of AP-somite polarity is mediated by the T-box transcription factor Tbx18, which appears to act downstream of Mesp2 and Delta/Notch signaling to maintain the separation of anterior and posterior somite compartments.
Abstract: The compartmentalization of somites along their anterior–posterior (AP) axis is pivotal to the segmental organization of the vertebrate axial skeleton and the peripheral nervous system. Anterior and posterior somite halves contribute to different vertebral elements. They are also characterized by different proliferation rates and properties with respect to neural crest cell migration and spinal nerve passage. AP-somite polarity is generated in the anterior presomitic mesoderm by Mesp2 and Delta/Notch signaling. Here, we demonstrate that maintenance of AP-somite polarity is mediated by the T-box transcription factor Tbx18. Mice deficient for Tbx18 show expansion of pedicles with transverse processes and proximal ribs, elements derived from the posterior lateral sclerotome. AP-somite polarity is established in Tbx18 mutant embryos but is not maintained. During somite maturation, posterior somite compartments expand most likely because of posterior cells invading the anterior somite half. In the anterior lateral sclerotome, Tbx18 acts as an antiapoptotic factor. Ectopic expression experiments suggest that Tbx18 can promote anterior at the expense of posterior somite compartments. In summary, Tbx18 appears to act downstream of Mesp2 and Delta/Notch signaling to maintain the separation of anterior and posterior somite compartments.

165 citations

Journal ArticleDOI
TL;DR: The phenotypic characterization of a new mouse model for congenital ureter malformation revealed the molecular pathway important for the formation of the functional mesenchymal coating of the ureters and showed that the Ureteral mesenchyme derives from a distinct cell population separated early in kidney development from that of other mesenchcyal cells of the renal system.
Abstract: Congenital malformations of the urinary tract are a major cause of renal failure in children and young adults. They are often caused by physical obstruction or by functional impairment of the peristaltic machinery of the ureter. The underlying molecular and cellular defects are, however, poorly understood. Here we present the phenotypic characterization of a new mouse model for congenital ureter malformation that revealed the molecular pathway important for the formation of the functional mesenchymal coating of the ureter. The gene encoding the T-box transcription factor Tbx18 was expressed in undifferentiated mesenchymal cells surrounding the distal ureter stalk. In Tbx18-/- mice, prospective ureteral mesenchymal cells largely dislocalized to the surface of the kidneys. The remaining ureteral mesenchymal cells showed reduced proliferation and failed to differentiate into smooth muscles, but instead became fibrous and ligamentous tissue. Absence of ureteral smooth muscles resulted in a short hydroureter and hydronephrosis at birth. Our analysis also showed that the ureteral mesenchyme derives from a distinct cell population that is separated early in kidney development from that of other mesenchymal cells of the renal system.

134 citations

Journal ArticleDOI
TL;DR: In vivo studies indicate that cardiac electrical forces are required to preserve cardiac chamber morphology and may act as a key epigenetic factor in cardiac remodeling.
Abstract: Electrical cardiac forces have been previously hypothesized to play a significant role in cardiac morphogenesis and remodeling. In response to electrical forces, cultured cardiomyocytes rearrange their cytoskeletal structure and modify their gene expression profile. To translate such in vitro data to the intact heart, we used a collection of zebrafish cardiac mutants and transgenics to investigate whether cardiac conduction could influence in vivo cardiac morphogenesis independent of contractile forces. We show that the cardiac mutant dcos226 develops heart failure and interrupted cardiac morphogenesis following uncoordinated ventricular contraction. Using in vivo optical mapping/calcium imaging, we determined that the dco cardiac phenotype was primarily due to aberrant ventricular conduction. Because cardiac contraction and intracardiac hemodynamic forces can also influence cardiac development, we further analyzed the dco phenotype in noncontractile hearts and observed that disorganized ventricular conduction could affect cardiomyocyte morphology and subsequent heart morphogenesis in the absence of contraction or flow. By positional cloning, we found that dco encodes Gja3/Cx46, a gap junction protein not previously implicated in heart formation or function. Detailed analysis of the mouse Cx46 mutant revealed the presence of cardiac conduction defects frequently associated with human heart failure. Overall, these in vivo studies indicate that cardiac electrical forces are required to preserve cardiac chamber morphology and may act as a key epigenetic factor in cardiac remodeling.

110 citations


Cited by
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Journal ArticleDOI
TL;DR: Dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases, and there is great interest in therapeutic strategies to counteract these perturbations.
Abstract: The role of non-coding RNAs (ncRNAs) in disease is best understood for microRNAs in cancer. However, there is increasing interest in the disease-related roles of other ncRNAs — including piRNAs, snoRNAs, T-UCRs and lncRNAs — and in using this knowledge for therapy.

4,016 citations

Journal ArticleDOI
TL;DR: Recent advances in the understanding of miRNAs in cancer and in other diseases are described and the challenge of identifying the most efficacious therapeutic candidates is discussed and a perspective on achieving safe and targeted delivery of miRNA therapeutics is provided.
Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

3,210 citations

Journal ArticleDOI
TL;DR: How cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts is described.
Abstract: Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic.

2,492 citations

Journal ArticleDOI
16 Mar 2012-Cell
TL;DR: Emerging principles of miRNA regulation of stress signaling pathways are reviewed and applied to the authors' understanding of the roles of miRNAs in disease.

1,491 citations

Journal ArticleDOI
TL;DR: This review guides the reader through important aspects of non-coding RNA biology, including their biogenesis, mode of actions, physiological function, as well as their role in the disease context (such as in cancer or the cardiovascular system).
Abstract: Advances in RNA-sequencing techniques have led to the discovery of thousands of non-coding transcripts with unknown function. There are several types of non-coding linear RNAs such as microRNAs (miRNA) and long non-coding RNAs (lncRNA), as well as circular RNAs (circRNA) consisting of a closed continuous loop. This review guides the reader through important aspects of non-coding RNA biology. This includes their biogenesis, mode of actions, physiological function, as well as their role in the disease context (such as in cancer or the cardiovascular system). We specifically focus on non-coding RNAs as potential therapeutic targets and diagnostic biomarkers.

1,238 citations