Molecular genetic analysis of glucocorticoid signaling during mouse development.

Glucocorticoids are important in a number of developmental processes in mammals around birth. The pathway of gluconeogenesis is activated in liver shortly after birth due to the combined effects of glucocorticoids and glucagon. We have defined the essential cis-regulatory elements directing hormone-dependent liver-specific expression of the gene for tyrosine aminotransferase, a key gluconeogenic enzyme. The hormone response elements synergize with cell-type specific elements. In the case of glucocorticoids, the glucocorticoid-dependent enhancer is composed 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 other 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 receptor (GR) in the perinatal period and earlier during development, we have studied the expression of the mouse GR gene. Expression of the gene is controlled by at least three promoters, one of which is only active in T-lymphocytes. Expression of GR mRNA has been detected as early as day 9.5 of mouse development. To specifically address the role of glucocorticoid signaling via the GR during development, we have disrupted the GR gene by homologous recombination in mouse embryonic stem cells. The majority of GR mutants die shortly after birth and analysis so far has revealed defects in lung, liver, and adrenal function.