Endocrine Abstracts

Germline and somatic gene targeting of genes for steroid hormone receptor allows the characterization of their functions as well as their molecular modes of action. For the glucocorticoid receptor (GR) multiple modes of action have been identified. The receptor activates expression of genes, e.g. for gluconeogenic enzymes in hepatocytes, by binding as a dimer to glucocorticoid response elements (GRE) as well as by interaction with Stat5, functioning as a coactivator for DNA-bound Stat5. This functional interdependence of GR and Stat5 is reflected by sharing one third of their target genes. The receptor is able to repress AP-1/NF kB-dependent expression of genes involved in inflammation by protein-protein interaction and inhibits proopiomelanocortian and prolactin expression via binding to negative GREs. Cre/loxP-mediated generation of somatic mutants of the mineralocorticoid receptor (MR) circumvents the early lethality observed after germline inactivation. Inactivation of MR in the forebrain leads to impaired hippocampal-dependent learning as evidenced in Morris water- and radial maze analyses. Normal circadian corticosterone levels indicate that the limbic MR is dispensable for the maintenance of basal hypothalamic-pituitary-adrenal axis activity. The mechanisms underlying the critical actions of estrogen in the secretion of the gonadotropin-releasing hormone (GnRH) are unknown. A neuron-specific ERa mutation in the forebrain leads to infertility and loss of the positive feedback effects of estrogen upon GnRH neurons. As GnRH neurons do not express ERa, these results indicate that ERa-expressing neuronal afferents to GnRH neurons are critical for the preovulatory GnRH/LH surge. These genetic approaches to evaluate steroid hormone receptor activity not only reveal novel neural functions of these regulatory molecules in gene expression, but also unprecedented modes of their activity.