Trends in Endocrinology & Metabolism
ConferencesThe Yin and Yang of Nuclear Receptors: Symposium on Nuclear Receptors in Brain, Oegstgeest, The Netherlands, 13–14 April 2000
Section snippets
Diversity of Nuclear Receptors
Initially, the NR family was confined to a limited number of receptors for steroid hormones, thyroid hormone (TH), vitamins and retinoic acids. However, in recent years, the family has expanded considerably. New family members were found by cDNA library screening and PCR-based homology screening techniques and, more recently, by making use of database-assisted similarity comparison of DNA and/or protein2. With the primary structure known, one can then determine similarities between and within
Mechanisms of Transcriptional Regulation
Traditionally, it is thought that NRs, upon binding of a ligand, bind as dimers to consensus response elements in the promoter region of specific genes and then alter the rate of gene transcription. However, research over the past decade has shown that many variations on this theme are possible4. These variations introduce diversity in NR actions and open up the possibility of graded responses.
An example of such variation is that binding of ligands is by no means a prerequisite for NR
Target Genes
One of the most interesting questions about NRs in brain regards the nature of target genes. New technologies, such as DNA microarrays and serial analysis of gene expression (SAGE), now allow large-scale screening of responsive genes.
Guido Zaman (Oss, The Netherlands) illustrated GR-induced changes in expression of genes, which are putatively involved in inflammatory responses, using DNA microarrays. Contrary to the high number of responsive genes that may be expected, only 112 out of 7000
Functional Effects from Gene to Behaviour
The classical endocrine approach to study NR function in vivo was to remove the gland that synthesizes the steroid and then substitute with the cognate receptor ligand at a known concentration. However, recent advances in gene technology now allow the generation of animals in which synthesis or function of specific NRs is impaired. François Tronche (Heidelberg, Germany) illustrated the power of new animal models ranging from complete GR-null mutants (which are not viable) to brain-specific GR
Clinical Implications and Future Perspectives
Diversity and impaired functionality of NRs may be relatively frequent phenomena in humans. Steven Lamberts (Rotterdam, The Netherlands) illustrated this point for the human GR. He pointed out that many patients show a clinical syndrome in the absence of large genetic defects, due, for example, to polymorphism of the GR or other deficits in the signalling pathway. For instance, several splice variants of the GR (i.e. GRα, GRβ and GRδ) are encountered in human tissue. In expression systems, the
Acknowledgements
The Symposium was supported by the thematic network EUROSTERONE: Steroids in Health and Disease QLRI-CT-1999-00762 (http://www.eurosterone.org), EC-Biotech 96-0179 and NV Organon.
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