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.