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Partner 4A Ècole Normale Supérieure de Lyon

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Nuclear receptors are one of the most abundant classes of transcriptional regulators in animals (metazoans). They regulate diverse functions, such as homeostasis, reproduction, development, or metabolism. Nuclear hormone receptors function as ligand activated transcription factors, thus providing a direct link between signalling molecules that control these processes and transcriptional responses.

The superfamily includes receptors for hydrophobic molecules such as steroid hormones (estrogens, glucocorticoids, progesterone, mineralocorticoids, androgens, vitamin D, ecdysone, oxysterols, bile acids etc.), retinoic acids (all-trans and 9-cis isoforms), thyroid hormones, fatty acids, leukotrienes and prostaglandins. A large number of nuclear receptors have also been identified by homology, but have no identified natural ligand, and are referred to as 'nuclear orphan receptors'.

As nuclear receptors bind small molecules which can easily be modified by drug design, and control functions associated with major diseases (e.g. cancer, osteoporosis, diabetes), they are promising pharmacological targets. The search of ligands for orphan receptors and the identification of novel signalling pathways has become a very active research field. The existence of many synthetic compounds that are found in industrial or agricultural products and that play a role of endocrine disruptors on NR signalling pathway offer an important perspective in terms in basic and applied research.

Since 1994 and even more since our arrival in Lyon in 1997, our team use the nuclear receptor superfamilly as a model to understand the mechanisms that govern genome evolution and to better delineate the main events that lead to diversification of gene families during evolution. 

For this, we are developing three main research areas:
1) The functional characterization of orphan nuclear receptors in order to decipher their physiological and/or developmental role. We focus our research on two groups of orphan receptors that are very different and illustrate very well the main problems raised by this field: (i) the ERRs (for Estrogen Receptor Related) that are orphan receptors very closely related to the estrogen receptors and that are probably receptors for a ligand that is still to be discovered. We are focussing our research on the role of the ERRs on bone development as well as on the connections between ERs and ERRs; (ii) The Rev-erbs that exhibit several sequence peculiarities and are probably true orphan receptors. Rev-erbs are playing an important role in the control of circadian clocks.

2) A comparative approach that allows us to trace back the role that nuclear receptors have played in evolution. We used two model organisms, amphioxus, the brother group of vertebrates and zebrafish a powerful developmental biology model to trace back the origin of modern hormonal systems in vertebrates. We also use the nuclear receptors as probes to study genomes structure and evolution. This comparative approach that we are applying systematically from the sequence level to more functional analysis is the real specificity of our laboratory. This is why we will continue in this direction by using the possibility offered by genomic research. More and more our group will perform comparative genomic analysis of the nuclear receptor superfamily. 

3) A bioinformatics approach. We are constructing a database of nuclear receptors, NUREBASE, which allows us not only to maintain the official NR nomenclature, but also include relevant evolutionary and functional information, such as phylogenies, species, protein domains or expression patterns. In addition to our efforts regarding database development, we realize that much information about nuclear receptors is to be found data mining the results of genomics projects, such as complete or near complete genomes, EST sequences, etc. This allow us to obtain useful informations on genome evolution but also on the major steps of NR evolution and on the origin of endocrine regulations

Contribution to CASCADE