Mingot J.,Institute Neurociencias |
Vega S.,Institute Neurociencias |
Nieto M.A.,Institute Neurociencias
Cell Reports | Year: 2013
Exportin5 mediates the nuclear export of double-stranded RNAs, including pre-microRNAs, adenoviral RNAs, and tRNAs. When tRNAs are aminoacylated, the Exportin5-aminoacyl (aa)-tRNA complex recruits and coexports the translation elongation factor eEF1A. Here, we show that eEF1A binds to Snail transcription factors when bound to their main target, the E-cadherin promoter, facilitating their export to the cytoplasm in association with the aa-tRNA-Exportin5 complex. Snail binds to eEF1A through the SNAG domain, a protein nuclear export signal present in several transcription factor families, and this binding is regulated by phosphorylation. Thus, we describe a nuclear role for eEF1A and provide a mechanism for protein nuclear export that attenuates the activity of SNAG-containing transcription factors
Reis S.D.S.,City College of New York |
Reis S.D.S.,Federal University of Ceará |
Hu Y.,City College of New York |
Babino A.,FCEN UBA |
And 6 more authors.
Nature Physics | Year: 2014
Networks in nature do not act in isolation, but instead exchange information and depend on one another to function properly. Theory has shown that connecting random networks may very easily result in abrupt failures. This finding reveals an intriguing paradox: if natural systems organize in interconnected networks, how can they be so stable? Here we provide a solution to this conundrum, showing that the stability of a system of networks relies on the relation between the internal structure of a network and its pattern of connections to other networks. Specifically, we demonstrate that if interconnections are provided by network hubs, and the connections between networks are moderately convergent, the system of networks is stable and robust to failure. We test this theoretical prediction on two independent experiments of functional brain networks (in task and resting states), which show that brain networks are connected with a topology that maximizes stability according to the theory.
Carmena A.,Institute Neurociencias
Small GTPases | Year: 2012
Members of the Ras superfamily of small guanosine triphosphatases (GTPases) function as key nodes within signaling networks in a remarkable range of cellular processes, including cell proliferation, differentiation, growth, cell-cell adhesion and apoptosis. We recently described a novel role for the Ras-like small GTPases Rap1 and Ral in regulating cortical polarity and spindle orientation during asymmetric neuroblast division in Drosophila. The participation of these proteins in promoting cell polarization seems to be a common theme throughout evolution.
Moreno-Bravo J.A.,Institute Neurociencias |
Perez-Balaguer A.,Institute Neurociencias |
Martinez-Lopez J.E.,Institute Neurociencias |
Aroca P.,University of Murcia |
And 3 more authors.
Brain Structure and Function | Year: 2014
Hindbrain rhombomeres in general are differentially specified molecularly by unique combinations of Hox genes with other developmental genes. Rhombomere 1 displays special features, including absence of Hox gene expression. It lies within the hindbrain range of the Engrailed genes (En1, En2), controlled by the isthmic organizer via diffusion of FGF8. It is limited rostrally by the isthmus territory, and caudally by rhombomere 2. It is double the normal size of any other rhombomere. Its dorsal part generates the cerebellar hemispheres and its ventral part gives rise to several populations, such as some raphe nuclei, the interpeduncular nucleus, the rhabdoid nucleus, anterior, dorsal, ventral and posterodorsal tegmental nuclei, the cholinergic pedunculopontine and laterodorsal tegmental nuclei, rostral parts of the hindbrain reticular formation, the locus coeruleus, and part of the lateral lemniscal and paralemniscal nuclei, among other formations. Some of these populations migrate tangentially before reaching their final positions. The morphogen Sonic Hedgehog (Shh) is normally released from the local floor plate and underlying notochord. In the present report we explore, first, whether Shh is required in the specification of these r1 populations, and, second, its possible role in the guidance of tangentially migrating neurons that approach the midline. Our results indicate that when Shh function is altered selectively in a conditional mutant mouse strain, most populations normally generated in the medial basal plate of r1 are completely absent. Moreover, the relocation of some neurons that normally originate in the alar plate and migrate tangentially into the medial basal plate is variously altered. In contrast, neurons that migrate radially (or first tangentially and then radially) into the lateral basal plate were not significantly affected. © 2013 Springer-Verlag.
Acloque H.,Institute Neurociencias |
Ocana O.,Institute Neurociencias |
Matheu A.,UK National Institute for Medical Research |
Rizzoti K.,UK National Institute for Medical Research |
And 3 more authors.
Developmental Cell | Year: 2011
In developing amniote embryos, the first epithelial-to-mesenchymal transition (EMT) occurs at gastrulation, when a subset of epiblast cells moves to the primitive streak and undergoes EMT to internalize and generate the mesoderm and the endoderm. We show that in the chick embryo this decision to internalize is mediated by reciprocal transcriptional repression of Snail2 and Sox3 factors. We also show that the relationship between Sox3 and Snail is conserved in the mouse embryo and in human cancer cells. In the embryo, Snail-expressing cells ingress at the primitive streak, whereas Sox3-positive cells, which are unable to ingress, ensure the formation of ectodermal derivatives. Thus, the subdivision of the early embryo into the two main territories, ectodermal and mesendodermal, is regulated by changes in cell behavior mediated by the antagonistic relationship between Sox3 and Snail transcription factors. © 2011 Elsevier Inc.
Da Ros V.G.,Institute Neurociencias |
Gutierrez-Perez I.,Institute Neurociencias |
Ferres-Marco D.,Institute Neurociencias |
Dominguez M.,Institute Neurociencias
PLoS Biology | Year: 2013
Fine-tuned Notch and Hedgehog signalling pathways via attenuators and dampers have long been recognized as important mechanisms to ensure the proper size and differentiation of many organs and tissues. This notion is further supported by identification of mutations in these pathways in human cancer cells. However, although it is common that the Notch and Hedgehog pathways influence growth and patterning within the same organ through the establishment of organizing regions, the cross-talk between these two pathways and how the distinct organizing activities are integrated during growth is poorly understood. Here, in an unbiased genetic screen in the Drosophila melanogaster eye, we found that tumour-like growth was provoked by cooperation between the microRNA miR-7 and the Notch pathway. Surprisingly, the molecular basis of this cooperation between miR-7 and Notch converged on the silencing of Hedgehog signalling. In mechanistic terms, miR-7 silenced the interference hedgehog (ihog) Hedgehog receptor, while Notch repressed expression of the brother of ihog (boi) Hedgehog receptor. Tumourigenesis was induced co-operatively following Notch activation and reduced Hedgehog signalling, either via overexpression of the microRNA or through specific down-regulation of ihog, hedgehog, smoothened, or cubitus interruptus or via overexpression of the cubitus interruptus repressor form. Conversely, increasing Hedgehog signalling prevented eye overgrowth induced by the microRNA and Notch pathway. Further, we show that blocking Hh signal transduction in clones of cells mutant for smoothened also enhance the organizing activity and growth by Delta-Notch signalling in the wing primordium. Together, these findings uncover a hitherto unsuspected tumour suppressor role for the Hedgehog signalling and reveal an unanticipated cooperative antagonism between two pathways extensively used in growth control and cancer. © 2013 Da Ros et al.
Nieto M.A.,Institute Neurociencias |
Cano A.,Uam Institute Investigaciones Biomedicas Alberto Sols Csic Uam
Seminars in Cancer Biology | Year: 2012
The epithelial to mesenchymal transition or EMT has become one of the most exciting fields in cancer research. Nevertheless, its relevance in tumor biology and the metastatic process still faces some controversy. Clarification may arise when considering the EMT as a reversible and often incomplete process, essentially a manifestation of strong epithelial plasticity. Transient cellular states are generated to fulfill specific requirements in each and all the steps of the metastatic process, from primary tumor cell detachment to dissemination and colonization. Opposing multiple cellular programs that promote or prevent EMT, thereby destabilizing or reinforcing epithelial integrity, play a central role in the inherent cellular dynamics of cancer progression. These cell biology programs not only drive cells towards the epithelial or the mesenchymal state but also impinge into multiple cellular and global responses including proliferation, stemness, chemo and immunotherapy resistance, inflammation and immunity, all relevant for the development of the metastatic disease. © 2012 Elsevier Ltd.
Darios F.,University of Cambridge |
Ruiperez V.,University of Cambridge |
Lopez I.,Institute Neurociencias |
Villanueva J.,Institute Neurociencias |
And 2 more authors.
EMBO Reports | Year: 2010
α-Synuclein is a synaptic modulatory protein implicated in the pathogenesis of Parkinson disease. The precise functions of this small cytosolic protein are still under investigation. α-Synuclein has been proposed to regulate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in vesicle fusion. Interestingly, α-synuclein fails to interact with SNARE proteins in conventional protein-binding assays, thus suggesting an indirect mode of action. As the structural and functional properties of both α-synuclein and the SNARE proteins can be modified by arachidonic acid, a common lipid regulator, we analysed this possible tripartite link in detail. Here, we show that the ability of arachidonic acid to stimulate SNARE complex formation and exocytosis can be controlled by α-synuclein, both in vitro and in vivo. α-Synuclein sequesters arachidonic acid and thereby blocks the activation of SNAREs. Our data provide mechanistic insights into the action of α-synuclein in the modulation of neurotransmission. © 2010 European Molecular Biology Organization.
Dominguez M.,Institute Neurociencias
Seminars in Cell and Developmental Biology | Year: 2014
The inappropriate Notch signalling can influence virtually all aspect of cancer, including tumour-cell growth, survival, apoptosis, angiogenesis, invasion and metastasis, although it does not do this alone. Hence, elucidating the partners of Notch that are active in cancer is now the focus of much intense research activity. The genetic toolkits available, coupled to the small size and short life of the fruit fly Drosophila melanogaster, makes this an inexpensive and effective animal model, suited to large-scale cancer gene discovery studies. The fly eye is not only a non-vital organ but its stereotyped size and disposition also means it is easy to screen for mutations that cause tumours and metastases and provides ample opportunities to test cancer theories and to unravel unanticipated nexus between Notch and other cancer genes, or to discover unforeseen Notch's partners in cancer. These studies suggest that Notch's oncogenic capacity is brought about not simply by increasing signal strength but through partnerships, whereby oncogenes gain more by cooperating than acting individually, as in a ring 'organized crime'. © 2014 Elsevier Ltd.
Garcia-Lopez R.,Institute Neurociencias |
Martinez S.,Institute Neurociencias
GLIA | Year: 2010
Oligodendrocytes are the myelin-forming cells in the central nervous system of vertebrates. Oligodendrocyte precursors arise from multiple restricted foci distributed along the antero-posterior axis of the developing brain. In chick and mouse embryos, oligodendrocyte precursors of the anterior forebrain emerge from neuroepithelial cells of the subpallium and migrate tangentially to invade the entire telencephalon (Olivier et al. (2001) Development 128:1757-1769). In the diencephalon, oligodendrocyte neuroepithelial precursors seem to be mainly located in the basal plate of caudal prosomeres, but very little is known about their distribution and maturation at later stages of embryonic development. Thus, in this work, we studied the origin and migration of oligodendrocyte precursos in the diencephalon of quail-chick chimeras. Homotopic and homochronic grafts demonstrated that, during embryonic development, diencephalic oligodendrocytes emerge from a common neuroepithelial domain in the basal plate of prosomere 1 and migrate tangentially, invading the dorsal regions of the diencephalic prosomeres and the telencephalon. © 2010 Wiley-Liss, Inc.