Institute for Molecular Biology

Mainz, Germany

Institute for Molecular Biology

Mainz, Germany
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Charalambous M.,University of Cambridge | Ferron S.R.,University of Cambridge | Da Rocha S.T.,University of Cambridge | Murray A.J.,University of Cambridge | And 4 more authors.
Cell Metabolism | Year: 2012

Neonatal survival in mammals is crucially dependent upon maintenance of body temperature. Neonatal body temperature is largely maintained by thermogenesis in brown adipose tissue (BAT). BAT develops perinatally in mice requiring integration of adipogenic and thermoregulatory gene pathways. We describe a regulatory mutation in the imprinted gene cluster on mouse chromosome 12 resulting in early postnatal lethality. Maternal inheritance of this mutation impairs the ability of young mice to maintain body temperature. While mechanisms of perinatal BAT development are well understood, our work highlights a second phase of BAT recruitment necessary to support small animals newly independent of the nest. We show that the imprinted delta-like homolog 1/preadipocyte factor (Dlk1/Pref1) and iodothyronine deiodinase type 3 (Dio3) functions converge on the development of brown fat at the transition to independent life. This shows that appropriate dosage control at imprinted loci can act as a critical determinant in postnatal survival during phases of physiological adaptation. © 2012 Elsevier Inc.

Swarts D.C.,Wageningen University | Makarova K.,U.S. National Center for Biotechnology Information | Wang Y.,CAS Institute of Biophysics | Nakanishi K.,Ohio State University | And 4 more authors.
Nature Structural and Molecular Biology | Year: 2014

Argonaute proteins are conserved throughout all domains of life. Recently characterized prokaryotic Argonaute proteins (pAgos) participate in host defense by DNA interference, whereas eukaryotic Argonaute proteins (eAgos) control a wide range of processes by RNA interference. Here we review molecular mechanisms of guide and target binding by Argonaute proteins, and describe how the conformational changes induced by target binding lead to target cleavage. On the basis of structural comparisons and phylogenetic analyses of pAgos and eAgos, we reconstruct the evolutionary journey of the Argonaute proteins through the three domains of life and discuss how different structural features of pAgos and eAgos relate to their distinct physiological roles. © 2014 Nature America, Inc.

Dietrich A.-C.,University of Potsdam | Dietrich A.-C.,Institute for Molecular Biology | Dietrich A.-C.,Max Delbrück Center for Molecular Medicine | Lombardo V.A.,University of Potsdam | And 5 more authors.
Developmental Cell | Year: 2014

During heart development, the onset of heartbeat and blood flow coincides with a ballooning of the cardiac chambers. Here, we have used the zebrafish as a vertebrate model to characterize chamber ballooning morphogenesis of the endocardium, a specialized population of endothelial cells that line the interior of the heart. By combining functional manipulations, fate mapping studies, and high-resolution imaging, we show that endocardial growth occurs without an influx of external cells. Instead, endocardial cell proliferation is regulated, both by blood flow and by Bmp signaling, in a manner independent of vascular endothelial growth factor (VEGF) signaling. Similar to myocardial cells, endocardial cells obtain distinct chamber-specific and inner- versus outer-curvature-specific surface area sizes. We find that the hemodynamic-sensitive transcription factor Klf2a is involved in regulating endocardial cell morphology. These findings establish the endocardium as the flow-sensitive tissue in the heart with a key role in adapting chamber growth in response to the mechanical stimulus of blood flow. © 2014 Elsevier Inc.

Giros A.,University of Valencia | Giros A.,Max Planck Institute of Biochemistry | Grgur K.,Max Planck Institute of Biochemistry | Gossler A.,Institute for Molecular Biology | Costell M.,University of Valencia
PLoS ONE | Year: 2011

The arginine-glycine-aspartate (RGD) motif in fibronectin (FN) represents the major binding site for α5β1 and αvβ3 integrins. Mice lacking a functional RGD motif in FN (FN RGE/RGE) or α5 integrin develop identical phenotypes characterized by embryonic lethality and a severely shortened posterior trunk with kinked neural tubes. Here we show that the FN RGE/RGE embryos arrest both segmentation and axis elongation. The arrest is evident at about E9.0, corresponding to a stage when gastrulation ceases and the tail bud-derived presomitic mesoderm (PSM) induces α5 integrin expression and assumes axis elongation. At this stage cells of the posterior part of the PSM in wild type embryos are tightly coordinated, express somitic oscillator and cyclic genes required for segmentation, and form a tapered tail bud that extends caudally. In contrast, the posterior PSM cells in FN RGE/RGE embryos lost their tight associations, formed a blunt tail bud unable to extend the body axis, failed to induce the synchronised expression of Notch1 and cyclic genes and cease the formation of new somites. Mechanistically, the interaction of PSM cells with the RGD motif of FN is required for dynamic formation of lamellipodia allowing motility and cell-cell contact formation, as these processes fail when wild type PSM cells are seeded into a FN matrix derived from FN RGE/RGE fibroblasts. Thus, α5β1-mediated adhesion to FN in the PSM regulates the dynamics of membrane protrusions and cell-to-cell communication essential for elongation and segmentation of the body axis. © 2011 Girós et al.

Bennet M.,Max Planck Institute of Colloids and Interfaces | Akiva A.,Weizmann Institute of Science | Faivre D.,Max Planck Institute of Colloids and Interfaces | Malkinson G.,Weizmann Institute of Science | And 4 more authors.
Biophysical Journal | Year: 2014

Confocal Raman microspectroscopy and fluorescence imaging are two well-established methods providing functional insight into the extracellular matrix and into living cells and tissues, respectively, down to single molecule detection. In living tissues, however, cells and extracellular matrix coexist and interact. To acquire information on this cell-matrix interaction, we developed a technique for colocalized, correlative multispectral tissue analysis by implementing high-sensitivity, wide-field fluorescence imaging on a confocal Raman microscope. As a proof of principle, we study early stages of bone formation in the zebrafish (Danio rerio) larvae because the zebrafish has emerged as a model organism to study vertebrate development. The newly formed bones were stained using a calcium fluorescent marker and the maturation process was imaged and chemically characterized in vivo. Results obtained from early stages of mineral deposition in the zebrafish fin bone unequivocally show the presence of hydrogen phosphate containing mineral phases in addition to the carbonated apatite mineral. The approach developed here opens significant opportunities in molecular imaging of metabolic activities, intracellular sensing, and trafficking as well as in vivo exploration of cell-tissue interfaces under (patho-)physiological conditions. © 2014 The Authors.

Ludtke T.H.-W.,Institute for Molecular Biology | Farin H.F.,Institute for Molecular Biology | Farin H.F.,Hubrecht Institute | Rudat C.,Institute for Molecular Biology | And 5 more authors.
PLoS Genetics | Year: 2013

Vertebrate organ development relies on the precise spatiotemporal orchestration of proliferation rates and differentiation patterns in adjacent tissue compartments. The underlying integration of patterning and cell cycle control during organogenesis is insufficiently understood. Here, we have investigated the function of the patterning T-box transcription factor gene Tbx2 in lung development. We show that lungs of Tbx2-deficient mice are markedly hypoplastic and exhibit reduced branching morphogenesis. Mesenchymal proliferation was severely decreased, while mesenchymal differentiation into fibrocytes was prematurely induced. In the epithelial compartment, proliferation was reduced and differentiation of alveolar epithelial cells type 1 was compromised. Prior to the observed cellular changes, canonical Wnt signaling was downregulated, and Cdkn1a (p21) and Cdkn1b (p27) (two members of the Cip/Kip family of cell cycle inhibitors) were strongly induced in the Tbx2-deficient lung mesenchyme. Deletion of both Cdkn1a and Cdkn1b rescued, to a large degree, the growth deficits of Tbx2-deficient lungs. Prolongation of Tbx2 expression into adulthood led to hyperproliferation and maintenance of mesenchymal progenitor cells, with branching morphogenesis remaining unaffected. Expression of Cdkn1a and Cdkn1b was ablated from the lung mesenchyme in this gain-of-function setting. We further show by ChIP experiments that Tbx2 directly binds to Cdkn1a and Cdkn1b loci in vivo, defining these two genes as direct targets of Tbx2 repressive activity in the lung mesenchyme. We conclude that Tbx2-mediated regulation of Cdkn1a and Cdkn1b represents a crucial node in the network integrating patterning information and cell cycle regulation that underlies growth, differentiation, and branching morphogenesis of this organ. © 2013 Lüdtke et al.

Kaaij L.J.T.,University Utrecht | Hoogstrate S.W.,University Utrecht | Berezikov E.,University Utrecht | Ketting R.F.,University Utrecht | Ketting R.F.,Institute for Molecular Biology
RNA | Year: 2013

Transposable elements (TEs) are mobile genetic elements that can have many deleterious effects on the fitness of their host. The germline-specific PIWI pathway guards the genome against TEs, deriving its specificity from sequence complementarity between PIWI-bound small RNAs (piRNAs) and the TEs. The piRNAs are derived from so-called piRNA clusters. Recent studies have demonstrated that the piRNA repertoire can be adjusted to accommodate recent TE invasions by capturing invading TEs in piRNA loci. Thus far, no information concerning piRNA divergence is available from vertebrates. We present piRNA analyses of two relatively divergent zebrafish strains. We find that significant differences in the piRNA populations have accumulated, most notably among active class I TEs. This divergence can be split into differences in piRNA abundance per element and differences in sense/antisense polarity ratios. In crosses between animals of the different strains, many of these differences are resolved in the progeny. However, some differences remain, often leaning to the maternally contributed piRNA population. These differences can be detected at least two generations later. Our data illustrate, for the first time, the fluidity of piRNA populations in vertebrates and how the established diversity is transmitted to future generations. Copyright © 2013 RNA Society.

Luteijn M.J.,University Utrecht | Ketting R.F.,University Utrecht | Ketting R.F.,Institute for Molecular Biology
Nature Reviews Genetics | Year: 2013

Small-RNA-guided gene regulation is a recurring theme in biology. Animal germ cells are characterized by an intriguing small-RNA-mediated gene-silencing mechanism known as the PIWI pathway. For a long time, both the biogenesis of PIWI-interacting RNAs (piRNAs) as well as their mode of gene silencing has remained elusive. A recent body of work is shedding more light on both aspects and implicates PIWI in the establishment of transgenerational epigenetic states. In fact, the epigenetic states imposed by PIWI on targets may actually drive piRNA production itself. These findings start to couple small RNA biogenesis with small-RNA-mediated epigenetics. © 2013 Macmillan Publishers Limited. All rights reserved.

Mueller N.,University of Würzburg | Avota E.,University of Würzburg | Collenburg L.,University of Würzburg | Grassme H.,Institute for Molecular Biology | Schneider-Schaulies S.,University of Würzburg
PLoS Pathogens | Year: 2014

T cell paralysis is a main feature of measles virus (MV) induced immunosuppression. MV contact mediated activation of sphingomyelinases was found to contribute to MV interference with T cell actin reorganization. The role of these enzymes in MV-induced inhibition of T cell activation remained equally undefined as their general role in regulating immune synapse (IS) activity which relies on spatiotemporal membrane patterning. Our study for the first time reveals that transient activation of the neutral sphingomyelinase 2 (NSM2) occurs in physiological co-stimulation of primary T cells where ceramide accumulation is confined to the lamellum (where also NSM2 can be detected) and excluded from IS areas of high actin turnover. Genetic ablation of the enzyme is associated with T cell hyper-responsiveness as revealed by actin dynamics, tyrosine phosphorylation, Ca2+-mobilization and expansion indicating that NSM2 acts to suppress overshooting T cell responses. In line with its suppressive activity, exaggerated, prolonged NSM2 activation as occurring in co-stimulated T cells following MV exposure was associated with aberrant compartmentalization of ceramides, loss of spreading responses, interference with accumulation of tyrosine phosphorylated protein species and expansion. Altogether, this study for the first time reveals a role of NSM2 in physiological T cell stimulation which is dampening and can be abused by a virus, which promotes enhanced and prolonged NSM2 activation to cause pathological T cell suppression. © 2014 Mueller et al.

Greulich F.,Institute for Molecular Biology | Rudat C.,Institute for Molecular Biology | Kispert A.,Institute for Molecular Biology
Cardiovascular Research | Year: 2011

The multi-chambered mammalian heart arises from a simple tube by polar elongation, myocardial differentiation and morphogenesis. Members of the large family of T-box (Tbx) transcription factors have been identified as crucial players that act in distinct subprogrammes during cardiac regionalization. Tbx1 and Tbx18 ensure elongation of the cardiac tube at the anterior and posterior pole, respectively. Tbx1 acts in the pharyngeal mesoderm to maintain proliferation of mesenchymal precursor cells for formation of a myocardialized and septated outflow tract. Tbx18 is expressed in the sinus venosus region and is required for myocardialization of the caval veins and the sinoatrial node. Tbx5 and Tbx20 function in the early heart tube and independently activate the chamber myocardial gene programme, whereas Tbx2 and Tbx3 locally repress this programme to favour valvuloseptal and conduction system development. Here, we summarize that these T-box factors act in different molecular circuits and control target gene expression using diverse molecular strategies including binding to distinct protein interaction partners. © 2011 The Author.

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