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Interplay between liganded and orphan nuclear receptors controls reproductive pathways
R Métivier1, Y Le Dréan, G Salbert
1UPRES-A CNRS 6026, Equipe d'Endocrinologie Moléculaire de la Reproduction, Université de Rennes, France.
Abstract:
Nuclear receptors are transcription factors that belong to an evolutionary ancient superfamily. These proteins, which are even present in primitive metazoans, are implicated in all levels of cell fate: proliferation, differentiation, and apoptosis. Some of these nuclear receptors behave as ligand-inducible transcription factors, as they have acquired during evolution the ability to bind ligands. This is the case for some proteins that recognize small hydrophobic signaling molecules, and particularly the estrogen receptor (ER or NR3A1), which regulates the target gene's transcription rate under estrogen binding. It is now known that the ER alone regulates the transcription of many genes, such as those implicated in reproductive functions. However, this ER-mediated signaling pathway could be modulated by other transcription factors. Our work has established that two other orphan nuclear receptors (SF-1 or NR5A1 and the COUP-TFs, NR2F1 and NR2F2) can enhance two ER-regulated genes implicated in salmonid reproductive functions: the ER gene itself, and the sGTHIIbeta gene. Moreover, some xenoestrogens could disturb these regulations. Therefore, our data contribute to the concept that interplay between nuclear receptors is an important event for the transcriptional regulation of genes controlling cellular functions.
Insights
Nuclear receptors regulate cell functions. This study shows orphan nuclear receptors enhance estrogen receptor-regulated genes, impacting salmonid reproduction and highlighting receptor interplay.
Area of Science:
- Molecular Biology
- Endocrinology
- Genetics
Background:
- Nuclear receptors are ancient transcription factors regulating cell fate (proliferation, differentiation, apoptosis).
- Estrogen receptor (ER) is a ligand-inducible nuclear receptor controlling gene transcription, particularly in reproductive functions.
- ER signaling pathways can be modulated by other transcription factors.
Purpose of the Study:
- To investigate the interaction between orphan nuclear receptors and ER-regulated genes in salmonid reproduction.
- To determine if SF-1 (NR5A1) and COUP-TFs (NR2F1, NR2F2) influence ER-regulated genes.
- To explore the potential impact of xenoestrogens on these regulatory mechanisms.
Main Methods:
- The study focused on analyzing the regulatory effects of specific nuclear receptors on key reproductive genes in salmonids.
- Experimental approaches likely involved gene expression analysis and potentially protein-ligand interaction studies (details not provided in abstract).
Main Results:
- Two orphan nuclear receptors, SF-1 (NR5A1) and COUP-TFs (NR2F1, NR2F2), were found to enhance the transcription of two ER-regulated genes.
- These enhanced genes include the estrogen receptor (ER) gene itself and the sGTHIIbeta gene, both critical for salmonid reproductive functions.
- The findings suggest that xenoestrogens may disrupt these intricate regulatory interactions.
Conclusions:
- Nuclear receptor interplay is crucial for the transcriptional regulation of genes involved in cellular functions, including reproduction.
- The identified interactions between SF-1, COUP-TFs, and ER-regulated genes provide new insights into reproductive endocrinology.
- These findings have implications for understanding the effects of environmental estrogens on endocrine disruption in aquatic species.