Cell Biology Group
Nuclear receptors constitute a superfamily of ligand-dependent transcription factors, which include receptors for steroid hormones, retinoids, thyroid hormone and eicosanoid metabolites, and orphan receptors. These receptors play critical roles in the regulation of embryonic development and of many physiological processes in the adult (see figure 1).
In addition, data have implicated nuclear receptors in a number of diseases, including inflammation, osteoporosis, and metabolic syndrome. Researchers use synthetic antagonists for several nuclear receptors to effectively treat asthma, diabetes, atherosclerosis and cancer. Chemicals in the environment can influence receptor signaling pathways directly by functioning as agonists or antagonists of receptors. This interaction may lead to untimely activation of receptors or disruption of receptor signaling. Inversely, nuclear receptors regulate the metabolism of xenobiotics and drugs (see figure 1).
The retinoid-related orphan receptors alpha, beta and gamma (RORα, β and γ , also referred to as NR1F1, 2 and 3, respectively) comprise a distinct subfamily of nuclear receptors. Study of ROR-deficient mice has implicated RORs in the regulation of a number of biological processes and revealed potential roles for these proteins in several pathologies. Mice disrupted in RORα expression display an ataxic phenotype caused by severe cerebellar neurodegeneration (see figure 2). In addition, RORα-deficient mice have thin bones, exhibit an altered immune response and develop atherosclerosis on a high fat diet.
Recently, studies of mice deficient in the expression of RORγ unveiled several important physiological functions for this orphan receptor. Mice deficient in RORγ lack all lymph nodes and Peyer's patches suggesting that RORγ is essential for the development of secondary lymphoid organs (see figure 2). The deficiency in these secondary lymphoid tissues is due to the absence of lymphoid tissue-inducer (Lti) cells. RORγ-deficient mice also exhibit defects in thymopoiesis. Thymocytes from RORγ knockout mice undergo accelerated apoptosis that is due to a suppression of the expression of Bcl-xL, an anti-apoptotic protein. These observations suggest that RORγ plays a role in controlling homeostasis during thymopoiesis.
Recent studies have implicated RORα and RORγ in the regulation of the adaptive immune response. Both RORα- and RORγ-deficient mice exhibit a decreased susceptibility to allergen-induced lung inflammation, which in the case of RORγ-deficient mice may be related, in part, to the absence of proinflammatory TH17 T-helper cells. Additional studies using gene profiling identified important roles for RORα and RORγ in the regulation of genes encoding several Phase I and Phase II metabolic enzymes in liver. These observations suggest that RORα and RORγ receptors have a critical function in the regulation of several metabolic pathways, including those involved in the metabolism of steroids, bile acids and xenobiotics. Therefore, they are important in the control of metabolic homeostasis.
Considering the potential roles for RORs in asthma, atherosclerosis, osteoporosis, inflammation and cancer, discovery of ROR ligands may lead to the development of novel and promising therapeutic strategies for these diseases.