Activation of the adult mode of ovine growth hormone receptor gene expression by cortisol during late fetal development

The developmental and tissue-specific regulation of growth hormone receptor (GI-W) mRNA expression is complex and involves alternate leader exon usage . The transcript composition of hepatic GHR mRNA has therefore been determi ned in fetal sheep during late gestation and after experimental manipulatio n of fetal plasma cortisol levels by fetal adrenalectomy and exogenous cort isol infusion, using RNase protection assays and a riboprobe containing exo ns 1A, 2, and 3 of the ovine GHR gene, Expression of the adult liver-specif ic GHR mRNA transcript containing exon 1A was not detected earlier than 138 days of gestation (term 145 +/- 2 days). Thereafter, expression of this le ader exon increased and accounted for 25-30% of the total GHR mRNA in the f etal liver at term, Hepatic GHR mRNA derived from leader exons other than 1 A was detectable at 97 days and increased in abundance toward term in paral lel with the normal prepartum rise in fetal plasma cortisol, Abolition of t his cortisol surge by fetal adrenalectomy prevented both the activation of exon 1A expression and the prepartum rise in GHR mRNA derived from the othe r leader exons in fetal ovine liver. Conversely, raising cortisol levels by exogenous infusion earlier in gestation prematurely activated exon 1A expr ession and enhanced the abundance of GHR mRNA transcripts derived from the other leader exons, Cortisol therefore appears to activate the adult mode o f GHR gene expression in fetal ovine liver during late gestation. These obs ervations have important implications for the maturation of the somatotroph ic axis and for the onset of GH-dependent growth after birth.