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San Juan de Alicante, Spain

Ferreiroa R.,University of Santiago de Compostela | Sanchez E.,University of Santiago de Compostela | Martinez L.,Institute Neurociencias Of Alicante
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2011

In the present work we propose a dynamic model of the lateral geniculate nucleus (dLGN) that allows the implementation of different configurations of the push-pull circuitry in order to study the spatio-temporal filtering being carried out. It is widely accepted that each relay neuron receives only one input from a single retinal ganglion cell, which leads to interpret that the thalamus preserves the retinal structure of the receptive field and thus works as a simple relay station. We believe that this assumption is not fully valid and the thalamus could perform a more relevant processing of information through its complex push-pull circuitry. To test this hypothesis, a computational model was developed with a wiring configuration (convergence/divergence) between the retina and the dLGN based on experimental evidences, and a realistic description of the ON and OFF channels of dLGN. We found that this configuration may help improve the contrast of a stimulus by increasing its synaptic weight on higher frequencies. © 2011 Springer-Verlag Berlin Heidelberg.

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.

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.

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.

Yu T.,Kings College London | Yaguchi Y.,Kings 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.

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