MOLECULAR-GENETIC ANALYSIS OF GLUCOCORTICOID SIGNALING DURING MOUSE DEVELOPMENT

Glucocorticoids are important in a number of developmental processes i n mammals around birth. The pathway of gluconeogenesis is activated in liver shortly after birth due to the combined effects of glucocortico ids and glucagon. We have defined the essential cis-regulatory element s directing hormone-dependent liver-specific expression of the gene fo r tyrosine aminotransferase, a key gluconeogenic enzyme. The hormone r esponse elements synergize with cell-type specific elements. In the ca se of glucocorticoids, the glucocorticoid-dependent enhancer is compos ed of the glucocorticoid response element and binding sites for liver cell-enriched transcription factors, in particular hepatocyte nuclear factor-3. The dependence of the respective enhancer motifs on each oth er restricts the hormonal activation of the tyrosine aminotransferase gene in liver in response to a hormonal signal. To further understand the role of glucocorticoid signaling via the type II glucocorticoid re ceptor (GR) in the perinatal period and earlier during development, we have studied the expression of the mouse GR gene. Expression of the g ene is controlled by at least three promoters, one of which is only ac tive in T-lymphocytes. Expression of GR mRNA has been detected as earl y as day 9.5 of mouse development. To specifically address the role of glucocorticoid signaling via the GR during development, we have disru pted the GR gene by homologous recombination in mouse embryonic stem c ells. The majority of GR mutants die shortly after birth and analysis so far has revealed defects in lung, liver, and adrenal function.