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Evry, France

Scerbo P.,French Natural History Museum | Scerbo P.,Aix - Marseille University | Markov G.V.,French Natural History Museum | Markov G.V.,CNRS Lyon Institute of Functional Genomics | And 7 more authors.
PLoS ONE | Year: 2014

Though pluripotency is well characterized in mammals, many questions remain to be resolved regarding its evolutionary history. A necessary prerequisite for addressing this issue is to determine the phylogenetic distributions and orthology relationships of the transcription factor families sustaining or modulating this property. In mammals, the NANOG homeodomain transcription factor is one of the core players in the pluripotency network. However, its evolutionary history has not been thoroughly studied, hindering the interpretation of comparative studies. To date, the NANOG family was thought to be monogenic, with numerous pseudogenes described in mammals, including a tandem duplicate in Hominidae. By examining a wide-array of craniate genomes, we provide evidence that the NANOG family arose at the latest in the most recent common ancestor of osteichthyans and that NANOG genes are frequently found as tandem duplicates in sarcopterygians and as a single gene in actinopterygians. Their phylogenetic distribution is thus reminiscent of that recently shown for Class V POU paralogues, another key family of pluripotency-controlling factors. However, while a single ancestral duplication has been reported for the Class V POU family, we suggest that multiple independent duplication events took place during evolution of the NANOG family. These multiple duplications could have contributed to create a layer of complexity in the control of cell competence and pluripotency, which could explain the discrepancies relative to the functional evolution of this important gene family. Further, our analysis does not support the hypothesis that loss of NANOG and emergence of the preformation mode of primordial germ cell specification are causally linked. Our study therefore argues for the need of further functional comparisons between NANOG paralogues, notably regarding the novel duplicates identified in sauropsids and non-eutherian mammals. © 2014 Scerbo et al.

Scerbo P.,French Natural History Museum | Scerbo P.,Aix - Marseille University | Girardot F.,French Natural History Museum | Vivien C.,French Natural History Museum | And 9 more authors.
PLoS ONE | Year: 2012

Vertebrate development requires progressive commitment of embryonic cells into specific lineages through a continuum of signals that play off differentiation versus multipotency. In mammals, Nanog is a key transcription factor that maintains cellular pluripotency by controlling competence to respond to differentiation cues. Nanog orthologs are known in most vertebrates examined to date, but absent from the Anuran amphibian Xenopus. Interestingly, in silico analyses and literature scanning reveal that basal vertebrate ventral homeobox (ventxs) and mammalian Nanog factors share extensive structural, evolutionary and functional properties. Here, we reassess the role of ventx activity in Xenopus laevis embryos and demonstrate that they play an unanticipated role as guardians of high developmental potential during early development. Joint over-expression of Xenopus ventx1.2 and ventx2.1-b (ventx1/2) counteracts lineage commitment towards both dorsal and ventral fates and prevents msx1-induced ventralization. Furthermore, ventx1/2 inactivation leads to down-regulation of the multipotency marker oct91 and to premature differentiation of blastula cells. Finally, supporting the key role of ventx1/2 in the control of developmental potential during development, mouse Nanog (mNanog) expression specifically rescues embryonic axis formation in ventx1/2 deficient embryos. We conclude that during Xenopus development ventx1/2 activity, reminiscent of that of Nanog in mammalian embryos, controls the switch of early embryonic cells from uncommitted to committed states. © 2012 Scerbo et al.

Pasquier D.,CNRS Developmental Biology Laboratory | Pasquier D.,University Pierre and Marie Curie | Pasquier D.,WatchFrog | Dupre A.,CNRS Developmental Biology Laboratory | And 3 more authors.
PLoS ONE | Year: 2011

Ovulated eggs possess maternal apoptotic execution machinery that is inhibited for a limited time. The fertilized eggs switch off this time bomb whereas aged unfertilized eggs and parthenogenetically activated eggs fail to stop the timer and die. To investigate the nature of the molecular clock that triggers the egg decision of committing suicide, we introduce here Xenopus eggs as an in vivo system for studying the death of unfertilized eggs. We report that after ovulation, a number of eggs remains in the female body where they die by apoptosis. Similarly, ovulated unfertilized eggs recovered in the external medium die within 72 h. We showed that the death process depends on both cytochrome c release and caspase activation. The apoptotic machinery is turned on during meiotic maturation, before fertilization. The death pathway is independent of ERK but relies on activating Bad phosphorylation through the control of both kinases Cdk1 and JNK. In conclusion, the default fate of an unfertilized Xenopus egg is to die by a mitochondrial dependent apoptosis activated during meiotic maturation. © 2011 Du Pasquier et al.

Agency: Cordis | Branch: FP7 | Program: MC-IAPP | Phase: PEOPLE-2007-3-1-IAPP | Award Amount: 1.66M | Year: 2008

SME RECEPTOR is a transfer of knowledge programme which will bring top scientists from industry and academia together to address key questions in nuclear receptor research. The programme of research, which is implemented through the two way exchange of researchers between three leading research organisations and three specialist innovative SMEs, will develop methodology to tackle one of the most pressing medical challenges in Europe characterization of the nuclear receptor role and the development of drugs targeting the complex symptoms characterized by the metabolic syndrome. SME RECEPTOR will exploit new opportunities for drug design provided by advances in bioinformatics and transgenic technology. This will enhance the understanding of basis mechanisms underlying nuclear receptor actions and their translation into the physiological regulation of diseases. Since cardiovascular toxicity is a major factor involved in both early and late drug failure, SME RECEPTOR will primarily focus on the development of early screening methods for cardiovascular toxicity, as well as to expand the knowledge of the governing molecular mechanisms. A key factor is the ability to translate the knowledge generated within this exchange programme into more advanced and efficient development of novel pharmaceuticals within the industry. The project will generate a group of scientists with unique knowledge and international expertise in nuclear receptor biology as well as nuclear receptor targeting pharmaceuticals. The mutually beneficial two way transfer of knowledge between industry and academia will provide a career boost to the researchers who will acquire leading new knowledge, complementary training and a detailed understanding of the research culture in their opposite sector. The project will further promote industry-academic networking, creating a strategic long-lasting industry-academia partnership.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2013-ITN | Award Amount: 4.02M | Year: 2013

The ability to manipulate cellular pluripotency and differentiation holds the as yet unrealized promise of regenerative medicine to produce replacement cells and tissues. To this end a deep understanding of the regulation of differentiation potential in the context of normal embryonic development is crucial. The recent revolution in sequencing technology has enabled high throughput and genome-wide analysis of cellular behaviour. The challenge with the new opportunities in genome-scale quantitative data gathering is to reach a more fundamental, systems level understanding of complex biological phenomena such as development and differentiation. The mission of the DevCom network is to train a new generation of promising scientists to bridge the gap between developmental and computational biology, and to prepare this generation for the emerging field of New Biology in which systems-level, quantitative and computational approaches are fully integrated in the analysis of profound scientific problems related to pluripotency and differentiation. The DevCom research plan revolves around early embryonic regulatory networks and disease networks in vertebrate embryos of the Xenopus and zebrafish model systems. The training plan involves interdisciplinary training with exposure to both academic and business settings. The trainees will acquire technical expertise in embryonic anatomy and development, genomic profiling, sequence conservation and evolutionary relationships of regulatory elements, genetic and chemical screens, mass spectrometry, informatics, statistics and computational modelling, and will be trained in a range of soft and complementary skills. Therefore the DevCom Training and Research Programmes are designed to foster readiness for leading roles in academia and industry and will have a lasting impact on the training programmes of participating institutions.

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