Centro Andaluz Of Biologia Del Desarrollo Cabd

Sevilla, Spain

Centro Andaluz Of Biologia Del Desarrollo Cabd

Sevilla, Spain

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PubMed | Helmholtz Center Munich, Bioinformatics Unit, Centro Andaluz Of Biologia Del Desarrollo Cabd, University of Western Australia and CIBER ISCIII
Type: Journal Article | Journal: Development (Cambridge, England) | Year: 2015

Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degree. Sporadic and hereditary microphthalmos have been associated with heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, which encodes a transcription factor with evolutionarily conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment in adult mice. By combining analysis of Meis1 loss-of-function and conditional Meis1 functional rescue with ChIP-seq and RNA-seq approaches we show that, in contrast to its preferential association with Hox-Pbx BSs in the trunk, Meis1 binds to Hox/Pbx-independent sites during optic cup development. In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway. In addition, Meis1 is required for eye patterning by controlling a set of eye territory-specific transcription factors, so that in Meis1(-/-) embryos boundaries among the different eye territories are shifted or blurred. We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations.


Torres-Nunez E.,CSIC - Institute of Marine Research | Cal L.,CSIC - Institute of Marine Research | Suarez-Bregua P.,CSIC - Institute of Marine Research | Suarez-Bregua P.,University of Vigo | And 4 more authors.
Developmental Dynamics | Year: 2015

Background: SPARC/osteonectin is an evolutionarily conserved matricellular protein that modulates cell-matrix interaction and cell function. In all vertebrates, SPARC is dynamically expressed during embryogenesis. However, the precise function of SPARC and the regulatory elements required for its expression in particular during early embryogenesis are largely unknown. Results: The present study was undertaken to explore the molecular mechanisms that regulate sparc gene expression by in vivo functional characterization of the sparc promoter and identification of possible putative regulatory elements that govern basal promoter activity. We report here transient expression analyses of eGFP expression from transgenic zebrafish containing a Sparc-iTol2-eGFP-BAC and/or 7.25 kb-sparc-Tol2-eGFP constructs. eGFP expression was specifically found in the notochord, otic vesicle, fin fold, intermediate cell mass, and olfactory placode of BAC and Tol2 transposon vectors injected embryos. Deletion analysis revealed that promoter activity resides in the unique 5′-untranslated intronic region. Computer-based analysis revealed a putative CpG island immediately proximal to the translation start site within the intron sequence. Global inhibition of methylation with 5-Aza-2-deoxycytidine promoted sparc expression in association with decreasing CpG methylation. Conclusions: Taken together, these data identify a contributory role for DNA methylation in regulating sparc expression in zebrafish embryogenesis. © 2015 Wiley Periodicals, Inc.


Cornes E.,Lhospitalet Of Llobregat | Cornes E.,University of Bordeaux 1 | Cornes E.,French Institute of Health and Medical Research | Porta-De-La-Riva M.,Lhospitalet Of Llobregat | And 14 more authors.
RNA | Year: 2015

Genes coding for members of the Sm-like (LSm) protein family are conserved through evolution from prokaryotes to humans. These proteins have been described as forming homo-or heterocomplexes implicated in a broad range of RNA-related functions. To date, the nuclear LSm2-8 and the cytoplasmic LSm1-7 heteroheptamers are the best characterized complexes in eukaryotes. Through a comprehensive functional study of the LSm family members, we found that lsm-1 and lsm-3 are not essential for C. elegans viability, but their perturbation, by RNAi or mutations, produces defects in development, reproduction, and motility. We further investigated the function of lsm-1, which encodes the distinctive protein of the cytoplasmic complex. RNA-seq analysis of lsm-1 mutants suggests that they have impaired Insulin/IGF-1 signaling (IIS), which is conserved in metazoans and involved in the response to various types of stress through the action of the FOXO transcription factor DAF-16. Further analysis using a DAF-16:GFP reporter indicated that heat stress-induced translocation of DAF-16 to the nuclei is dependent on lsm-1. Consistent with this, we observed that lsm-1 mutants display heightened sensitivity to thermal stress and starvation, while overexpression of lsm-1 has the opposite effect. We also observed that under stress, cytoplasmic LSm proteins aggregate into granules in an LSM-1-dependent manner. Moreover, we found that lsm-1 and lsm-3 are required for other processes regulated by the IIS pathway, such as aging and pathogen resistance. © 2015 Mefferd et al.


Amore G.,Stazione Zoologica Anton Dohrn | Casares F.,Centro Andaluz Of Biologia Del Desarrollo Cabd
Developmental Biology | Year: 2010

Organ development is a complex process in which the activity of scores of interacting transcription factors and signaling pathways need to be integrated with proliferative growth. Developmental gene regulatory networks (GRNs) allow capturing essential regulatory pathways at a systems-level and provide an effective way of approaching such complexity. However typical GRNs studies focus on very early embryonic stages (usually pre-gastrulation) or late stages, when there is little or no cell proliferation, and therefore do not consider how organ growth is integrated in the developmental process. This can be conveniently investigated in the Drosophila melanogaster eye primordium. Here we present a working model meant to illustrate how during a critical period, the second larval stage, changes in cells' proliferative pattern are coordinated with the initiation of the Retinal Determination (RD) gene program. Such changes are regulated in response to two different sources of signal (Wnt1/. wg and BMP2/4/. dpp) produced by the anterior and posterior ends of the primordium, respectively. The dpp signaling is necessary to trigger the RD program. However in order for it to be effective, cells receiving Dpp have to be out of the wg signaling range. This is obtained thanks to the proliferative growth that precedes the onset of RD expression. With this network model many of the gene regulatory steps previously known to participate in growth and patterning are linked. Analysis of the model highlights a few essential regulatory principles, as well as poses new questions. In addition, these principles might operate during the growth and patterning of other organs. © 2010 Elsevier Inc.


Bras-Pereira C.,Instituto Gulbenkian Of Ciencia | Potier D.,Catholic University of Leuven | Jacobs J.,Catholic University of Leuven | Aerts S.,Catholic University of Leuven | And 2 more authors.
PLoS Genetics | Year: 2016

Proper organ patterning depends on a tight coordination between cell proliferation and differentiation. The patterning of Drosophila retina occurs both very fast and with high precision. This process is driven by the dynamic changes in signaling activity of the conserved Hedgehog (Hh) pathway, which coordinates cell fate determination, cell cycle and tissue morphogenesis. Here we show that during Drosophila retinogenesis, the retinal determination gene dachshund (dac) is not only a target of the Hh signaling pathway, but is also a modulator of its activity. Using developmental genetics techniques, we demonstrate that dac enhances Hh signaling by promoting the accumulation of the Gli transcription factor Cubitus interruptus (Ci) parallel to or downstream of fused. In the absence of dac, all Hh-mediated events associated to the morphogenetic furrow are delayed. One of the consequences is that, posterior to the furrow, dac- cells cannot activate a Roadkill-Cullin3 negative feedback loop that attenuates Hh signaling and which is necessary for retinal cells to continue normal differentiation. Therefore, dac is part of an essential positive feedback loop in the Hh pathway, guaranteeing the speed and the accuracy of Drosophila retinogenesis. © 2016 Brás-Pereira et al.


Bogdanovic O.,Centro Andaluz Of Biologia Del Desarrollo Cabd | Fernandez-Minan A.,Centro Andaluz Of Biologia Del Desarrollo Cabd | Tena J.J.,Centro Andaluz Of Biologia Del Desarrollo Cabd | De La Calle-Mustienes E.,Centro Andaluz Of Biologia Del Desarrollo Cabd | And 5 more authors.
Genome Research | Year: 2012

The generation of distinctive cell types that form different tissues and organs requires precise, temporal and spatial control of gene expression. This depends on specific cis-regulatory elements distributed in the noncoding DNA surrounding their target genes. Studies performed on mammalian embryonic stem cells and Drosophila embryos suggest that active enhancers form part of a defined chromatin landscape marked by histone H3 lysine 4 mono-methylation (H3K4me1) and histone H3 lysine 27 acetylation (H3K27ac). Nevertheless, little is known about the dynamics and the potential roles of these marks during vertebrate embryogenesis. Here, we provide genomic maps of H3K4me1/me3 and H3K27ac at four developmental time-points of zebrafish embryogenesis and analyze embryonic enhancer activity. We find that (1) changes in H3K27ac enrichment at enhancers accompany the shift from pluripotency to tissue-specific gene expression, (2) in early embryos, the peaks of H3K27ac enrichment are bound by pluripotent factors such as Nanog, and (3) the degree of evolutionary conservation is higher for enhancers that become marked by H3K27ac at the end of gastrulation, suggesting their implication in the establishment of the most conserved (phylotypic) transcriptome that is known to occur later at the pharyngula stage. © 2012, Published by Cold Spring Harbor Laboratory Press.


Santos J.S.,Centro Andaluz Of Biologia Del Desarrollo Cabd | Santos J.S.,Institute Biologia Molecular e Celular IBMC | Santos J.S.,Abel Salazar Biomedical Sciences Institute | Fonseca N.A.,INESC Porto | And 4 more authors.
Developmental Dynamics | Year: 2010

The tshz genes comprise a family of evolutionarily conserved transcription factors. However, despite the major role played by Drosophila tsh during the development of the fruit fly, the expression and function of other tshz genes have been analyzed in a very limited set of organisms and, therefore, our current knowledge of these genes is still fragmentary. In this study, we perform detailed phylogenetic analyses of the tshz genes, identify the members of this gene family in zebrafish and describe the developmental expressions of two of them, tshz2 and tshz3b, and compare them with meis1, meis2.1, meis2.2, pax6a, and pax6b expression patterns. The expression patterns of these genes define a complex set of coexpression domains in the developing zebrafish brain where their gene products have the potential to interact. © 2010 Wiley-Liss, Inc.


Brockmann A.,Centro Andaluz Of Biologia Del Desarrollo Cabd | Dominguez-Cejudo M.A.,Centro Andaluz Of Biologia Del Desarrollo Cabd | Amore G.,Stazione Zoologica Anton Dohrn | Casares F.,Centro Andaluz Of Biologia Del Desarrollo Cabd
Developmental Dynamics | Year: 2011

The retinal determination gene network (RDGN) constitutes a paradigm of a gene network controlling organ specification and growth. In this study, we probed the RDGN in the Drosophila ocelli, a set of simple eyes located on the fly's dorsal head, by studying the expression, regulation, and function of toy, hth, eya, and so, members of the Pax6, Meis, Eya, and Six gene families. Our results highlight the role of the pax6 gene toy, together with the hh signaling pathway, in the initiation of eya and so expression; the engagement of eya and so in a feedback loop necessary for their full expression; and the interplay between hh signaling and hth as a mechanism of organ size control, as general regulatory steps in the specification of visual organs. © 2010 Wiley-Liss, Inc.


PubMed | Centro Andaluz Of Biologia Del Desarrollo Cabd
Type: Journal Article | Journal: Developmental dynamics : an official publication of the American Association of Anatomists | Year: 2010

The tshz genes comprise a family of evolutionarily conserved transcription factors. However, despite the major role played by Drosophila tsh during the development of the fruit fly, the expression and function of other tshz genes have been analyzed in a very limited set of organisms and, therefore, our current knowledge of these genes is still fragmentary. In this study, we perform detailed phylogenetic analyses of the tshz genes, identify the members of this gene family in zebrafish and describe the developmental expressions of two of them, tshz2 and tshz3b, and compare them with meis1, meis2.1, meis2.2, pax6a, and pax6b expression patterns. The expression patterns of these genes define a complex set of coexpression domains in the developing zebrafish brain where their gene products have the potential to interact.


PubMed | Centro Andaluz Of Biologia Del Desarrollo Cabd and Instituto Gulbenkian Of Ciencia
Type: Journal Article | Journal: Development (Cambridge, England) | Year: 2015

The Drosophila transcriptional co-activator protein Yorkie and its vertebrate orthologs YAP and TAZ are potent oncogenes, whose activity is normally kept in check by the upstream Hippo kinase module. Upon its translocation into the nucleus, Yorkie forms complexes with several tissue-specific DNA-binding partners, which help to define the tissue-specific target genes of Yorkie. In the progenitor cells of the eye imaginal disc, the DNA-binding transcription factor Homothorax is required for Yorkie-promoted proliferation and survival through regulation of the bantam microRNA (miRNA). The transit from proliferating progenitors to cell cycle quiescent precursors is associated with the progressive loss of Homothorax and gain of Dachshund, a nuclear protein related to the Sno/Ski family of co-repressors. We have identified Dachshund as an inhibitor of Homothorax-Yorkie-mediated cell proliferation. Loss of dachshund induces Yorkie-dependent tissue overgrowth. Conversely, overexpressing dachshund inhibits tissue growth, prevents Yorkie or Homothorax-mediated cell proliferation of disc epithelia and restricts the transcriptional activity of the Yorkie-Homothorax complex on the bantam enhancer in Drosophila cells. In addition, Dachshund collaborates with the Decapentaplegic receptor Thickveins to repress Homothorax and Cyclin B expression in quiescent precursors. The antagonistic roles of Homothorax and Dachshund in Yorkie activity, together with their mutual repression, ensure that progenitor and precursor cells are under distinct proliferation regimes. Based on the crucial role of the human dachshund homolog DACH1 in tumorigenesis, our work suggests that DACH1 might prevent cellular transformation by limiting the oncogenic activity of YAP and/or TAZ.

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