San Juan de Alicante, Spain
San Juan de Alicante, Spain

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Brotons-Mas J.R.,IDIBAPS | Brotons-Mas J.R.,Institute Neurociencias Of Alicante | Brotons-Mas J.R.,Trinity College Dublin | Brotons-Mas J.R.,Instituto Cajal | And 6 more authors.
European Journal of Neuroscience | Year: 2010

Although hippocampal CA1 place cells can be strongly modulated by visual inputs, the effect of visual modulation on place cells in other areas of the hippocampal formation, such as the subiculum, has been less extensively explored. Here, we investigated the role of visual inputs on the activity of subicular place cells by manipulating ambient light levels while freely-moving rats foraged for food. Rats were implanted with tetrodes in the dorsal subiculum and units were recorded while the animal performed a pellet-chasing task during multiple light-to-dark and dark-to-light transitions. We found that subicular place fields presented a somewhat heterogeneous response to light-dark transitions, with 45% of pyramidal units showing stable locational firing across multiple light-dark-light transitions. These data suggest that visual inputs may participate in spatial information processing by the subiculum. However, as a plurality of units was stable across light-dark transitions, we suggest that the subiculum supports, probably in association with the grid cells of the entorhinal cortex, the neurocognitive processing underlying path integration. © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.


Mey A.,CNRS Lyon Institute of Functional Genomics | Acloque H.,Institute Neurociencias Of Alicante | Acloque H.,French National Institute for Agricultural Research | Lerat E.,University of Lyon | And 9 more authors.
Retrovirology | Year: 2012

Background: Long terminal repeats (LTR) from endogenous retroviruses (ERV) are source of binding sites for transcription factors which affect the host regulatory networks in different cell types, including pluripotent cells. The embryonic epiblast is made of pluripotent cells that are subjected to opposite transcriptional regulatory networks to give rise to distinct embryonic and extraembryonic lineages. To assess the transcriptional contribution of ERV to early developmental processes, we have characterized in vitro and in vivo the regulation of ENS-1, a host adopted and developmentally regulated ERV that is expressed in chick embryonic stem cells.Results: We show that Ens-1 LTR activity is controlled by two transcriptional pathways that drive pluripotent cells to alternative developmental fates. Indeed, both Nanog that maintains pluripotency and Gata4 that induces differentiation toward extraembryonic endoderm independently activate the LTR. Ets coactivators are required to support Gata factors' activity thus preventing inappropriate activation before epigenetic silencing occurs during differentiation. Consistent with their expression patterns during chick embryonic development, Gata4, Nanog and Ets1 are recruited on the LTR in embryonic stem cells; in the epiblast the complementary expression of Nanog and Gata/Ets correlates with the Ens-1 gene expression pattern; and Ens-1 transcripts are also detected in the hypoblast, an extraembryonic tissue expressing Gata4 and Ets2, but not Nanog. Accordingly, over expression of Gata4 in embryos induces an ectopic expression of Ens-1.Conclusion: Our results show that Ens-1 LTR have co-opted conditions required for the emergence of extraembryonic tissues from pluripotent epiblasts cells. By providing pluripotent cells with intact binding sites for Gata, Nanog, or both, Ens-1 LTR may promote distinct transcriptional networks in embryonic stem cells subpopulations and prime the separation between embryonic and extraembryonic fates. © 2012 Mey et al; licensee BioMed Central Ltd.


Mulero M.,Institute Hospital del Mar dInvestigacions Mediques IMIM | Ferres-Marco D.,Institute Neurociencias Of Alicante | Islam A.,University Pompeu Fabra | Islam A.,University of Dhaka | And 25 more authors.
Cancer Cell | Year: 2013

IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNFα. Mutations in the Drosophila IκBα gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-κB. Oncogenic transformation of keratinocytes results in cytoplasmic IκBα translocation associated with a massive activation of Hox. Accumulation of cytoplasmic IκBα was found in squamous cell carcinoma (SCC) associated with IKK activation and HOX upregulation. © 2013 Elsevier Inc.


Yu T.,King's College London | Yaguchi Y.,King's College London | Yaguchi Y.,Jikei University School of Medicine | Echevarria D.,Institute Neurociencias Of Alicante | And 2 more authors.
Development | Year: 2011

Fibroblast growth factors (FGFs) and regulators of the FGF signalling pathway are expressed in several cell types within the cerebellum throughout its development. Although much is known about the function of this pathway during the establishment of the cerebellar territory during early embryogenesis, the role of this pathway during later developmental stages is still poorly understood. Here, we investigated the function of sprouty genes (Spry1, Spry2 and Spry4), which encode feedback antagonists of FGF signalling, during cerebellar development in the mouse. Simultaneous deletion of more than one of these genes resulted in a number of defects, including mediolateral expansion of the cerebellar vermis, reduced thickness of the granule cell layer and abnormal foliation. Analysis of cerebellar development revealed that the anterior cerebellar neuroepithelium in the early embryonic cerebellum was expanded and that granule cell proliferation during late embryogenesis and early postnatal development was reduced. We show that the granule cell proliferation deficit correlated with reduced sonic hedgehog (SHH) expression and signalling. A reduction in Fgfr1 dosage during development rescued these defects, confirming that the abnormalities are due to excess FGF signalling. Our data indicate that sprouty acts both cell autonomously in granule cell precursors and non-cell autonomously to regulate granule cell number. Taken together, our data demonstrate that FGF signalling levels have to be tightly controlled throughout cerebellar development in order to maintain the normal development of multiple cell types. © 2011.


Martinez-Frias M.L.,Institute Salud Carlos III ISCIII | Martinez-Frias M.L.,CIBER ISCIII | Martinez-Frias M.L.,Complutense University of Madrid | De Frutos C.A.,Institute Neurociencias Of Alicante | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

Achondroplasia (ACH), thanatophoric dysplasia (TD) types I and II, hypochondroplasia (HCH), and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) are all due to activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We review the clinical, epidemiological, radiological, molecular aspects, and signaling pathways involved in these conditions. It is known that FGFR3 signaling is essential to regulate bone growth. The signal transducers and activators of transcription (STAT1) pathway is involved in the inhibition of chondrocyte proliferation, and the mitogen -activated protein kinase (MAPK) pathways are involved in chondrocyte differentiation. Hence, FGFR3 signaling is pivotal in chondrocyte differentiation and proliferation through these two different active pathways. Recent studies on the molecular mechanisms involved in chondrocyte differentiation and proliferation, demonstrated that Snail1 participates in the control of longitudinal bone growth and appears to be essential to transduce FGFR3 signaling during chondrogenesis. This result was confirmed in a newborn infant with TD, and suggests new nonsurgical therapeutic approaches, that is, Snail1 as a new encouraging therapeutic target. © 2009 Wiley-Liss, Inc.


Lopez-Novoa J.M.,University of Salamanca | Grande M.T.,University of Salamanca | Fuentes-Calvo I.,University of Salamanca | Arevalo M.,University of Salamanca | And 5 more authors.
Kidney International | Year: 2010

Tubulointerstitial fibrosis is characterized by the presence of myofibroblasts that contribute to extracellular matrix accumulation. These cells may originate from resident fibroblasts, bone-marrow-derived cells, or renal epithelial cells converting to a mesenchymal phenotype. Ras GTPases are activated during renal fibrosis and play crucial roles in regulating both cell proliferation and TGF-Β-induced epithelial-mesenchymal transition. Here we set out to assess the contribution of Ras to experimental renal fibrosis using the well-established model of unilateral ureteral obstruction. Fifteen days after obstruction, both fibroblast proliferation and inducers of epithelial-mesenchymal transition were lower in obstructed kidneys of H-ras knockout mice and in fibroblast cell lines derived from these mice. Interestingly, fibronectin, collagen I accumulation, overall interstitial fibrosis, and the myofibroblast population were also lower in the knockout than in the wild-type mice. As expected, we found lower levels of activated Akt in the kidneys and cultured fibroblasts of the knockout. Whether Ras inhibition will turn out to prevent progression of renal fibrosis will require more direct studies. © 2010 International Society of Nephrology.


Gontijo A.M.,Institute Neurociencias Of Alicante | Miguela V.,Institute Neurociencias Of Alicante | Whiting M.F.,Brigham Young University | Woodruff R.C.,Bowling Green State University | Dominguez M.,Institute Neurociencias Of Alicante
Nature Communications | Year: 2011

Genomes can encode a variety of proteins with unrelated architectures and activities. It is known that protein-coding genes of de novo origin have significantly contributed to this diversity. However, the molecular mechanisms and evolutionary processes behind these originations are still poorly understood. Here we show that the last 102 codons of a novel gene, Noble, assembled directly from non-coding DNA following an intronic deletion that induced alternative intron retention at the Drosophila melanogaster Rieske Iron Sulphur Protein (RFeSP) locus. A systematic analysis of the evolutionary processes behind the origin of Noble showed that its emergence was strongly biased by natural selection on and around the RFeSP locus. Noble mRNA is shown to encode a bona fide protein that lacks an iron sulphur domain and localizes to mitochondria. Together, these results demonstrate the generation of a novel protein at a naturally selected site. © 2011 Macmillan Publishers Limited. All rights reserved.


PubMed | Institute Neurociencias Of Alicante and University College London
Type: | Journal: Development (Cambridge, England) | Year: 2017

Snail and Zeb transcription factors induce epithelial to mesenchymal transition (EMT) in embryonic and adult tissues by direct repression of E-Cadherin transcription. The repression of E-Cadherin transcription by the EMT inducers Snail1 and Zeb2 plays a fundamental role in defining embryonic territories in the mouse, as E-Cadherin needs to be downregulated in the primitive streak and in the epiblast concomitant with the formation of mesendodermal precursors and the neural plate, respectively. Here we show that in the chick embryo, E-Cadherin is weakly expressed in the epiblast at pre-primitive streak stages where it is substituted by P-Cadherin We also show that Snail2 and Zeb2 repress P-Cadherin transcription in the primitive streak and the neural plate, respectively. This indicates that E- and P-Cadherin expression patterns evolved differently between chick and mouse. As such, the Snail1/E-Cadherin axis described in the early mouse embryo corresponds to Snail2/P-Cadherin in the chick, but both Snail factors and Zeb2 fulfill a similar role in chick and mouse in directly repressing ectodermal Cadherins to promote the delamination of mesendodermal precursors at gastrulation and the proper specification of the neural ectoderm during neural induction.


Rodrigues R.J.,Institute Neurociencias Of Alicante | Lerma J.,Institute Neurociencias Of Alicante
Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | Year: 2012

Kainate receptors (KARs) are members of the ionotropic glutamate receptor family. Despite their ubiquitous presence in the central nervous system, and in contrast to the better characterized N-methyl-d-aspartates (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), the contribution of KARs to synaptic transmission has only been demonstrated in a few central synapses. However, there is now accumulating evidence that KARs are present on both sides of the synapse, where they play distinct and diverse roles. In addition to their contribution to synaptic transmission, KARs can regulate synaptic activity and plasticity either by presynaptically modulating neurotransmitter release at GABAergic and glutamatergic synapses, or by postsynaptically regulating neuronal excitability. This prominent neuromodulatory role of KARs has been further highlighted by the finding that these glutamate-gated ion-channels can also signal through G-proteins and other second messengers. This non-canonical metabotropic signaling of KARs was firmly established by demonstrating it to be independent of ion flux. The discovery of this dual signaling capacity of KARs constituted a breakthrough in understanding how they function and since then, an increasing number of metabotropic actions of KARs have been reported. It is now clear that this dual signaling underlies the diverse functions of KARs and defining this metabotropic component of the signaling system operated by KARs will be necessary to understand the physiological contributions of glutamate receptors. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Slovakova J.,Institute Neurociencias Of Alicante | Carmena A.,Institute Neurociencias Of Alicante
Development | Year: 2011

Vertebrates and insects alike use glial cells as intermediate targets to guide growing axons. Similar to vertebrate oligodendrocytes, Drosophila midline glia ensheath and separate axonal commissures. Neuron-glia interactions are crucial during these events, although the proteins involved remain largely unknown. Here, we show that Canoe (Cno), the Drosophila ortholog of AF-6, and the DE-cadherin Shotgun (Shg) are highly restricted to the interface between midline glia and commissural axons. cno mutant analysis, genetic interactions and co-immunoprecipitation assays unveil Cno function as a novel regulator of neuronglia interactions, forming a complex with Shg, Wrapper and Neurexin IV, the homolog of vertebrate Caspr/paranodin. Our results also support additional functions of Cno, independent of adherens junctions, as a regulator of adhesion and signaling events in non-epithelial tissues. © 2011. Published by The Company of Biologists Ltd.

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