Cortisol up-regulates corticotropin releasing factor gene expression in the fetal ovine brainstem at 0.70 gestation

• Published in: Brain research. Molecular brain research. 1995-08, Vol.32 (1), p.75-81
• Main Authors: Keiger, C. Jane, O'Steen, W. Keith, Brewer, Gary, Sorci-Thomas, Mary, Zehnder, Timothy J., Rose, James C.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Biological and medical sciences; Brain - embryology; Brain - metabolism; Brain Stem - embryology; Brain Stem - metabolism; Corticotropin-Releasing Hormone - genetics; Development; Embryology: invertebrates and vertebrates. Teratology; Embryonic and Fetal Development - genetics; Embryonic and Fetal Development - physiology; Fetal Organ Maturity; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - physiology; Gestational Age; Glucocorticoid; Hydrocortisone - blood; Hydrocortisone - physiology; Medulla oblongata; Mesencephalon; Molecular embryology; Pons; Ribonuclease-protection assay; RNA, Messenger - biosynthesis; Sheep; Up-Regulation - genetics
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/0169-328X(95)00061-V

Glucocorticoids are important for the development of the central nervous system. In the ovine fetus, increased levels of plasma cortisol at term provide a stimulus to initiate parturition. CRF is central to this event in that it is one of the main modulators of the hypothalamic-pituitary-adrenal (HPA) axis. The purpose of the present study was to determine the effect of physiological increases in fetal plasma cortisol levels on corticotropin-releasing factor (CRF) gene expression in the developing ovine brain. Fetal plasma cortisol levels were chronically elevated at 0.70 gestation (100 days) to physiological levels found at 0.90 gestation (130 days; term 145 ± 2 days) when glucocorticoid-induced maturational changes are known to occur in the HPA axis. The 3′ end of the ovine CRF gene encodes 4 putative polyadenylation (poly(A)) signals that may post-transcriptionally regulate gene expression through stability, translation and localization of the mRNA in a temporal and spatial manner. To determine whether CRF mRNA levels or poly(A) site usage are differentially regulated by cortisol in a region-specific manner, we used an RNase protection assay with an antisense CRF RNA probe from the 3′ coding and untranslated regions of the gene to quantify changes in mRNA levels in the hypothalamus (Hypo), hippocampal-amygdala complex (H and A), frontal cerebral cortex (FCC) and brainstem. Our novel finding was a 3.5-fold increase in CRF mRNA levels in the medulla oblongata of fetuses from the cortisol group compared to those from the saline group ( P = 0.001). CRF mRNA levels in the Hypo, H and A and FCC did not change significantly in fetuses from the cortisol group. CRF mRNA transcripts derived from alternative poly(A) site usage were observed in all brain regions examined; however, cortisol administration did not change the ratio of mRNAs polyadenylated at site 1 versus sites 2–4. These results indicate that changes in the environment (e.g. physiological increases in fetal plasma cortisol levels at an earlier time during development) have regional effects on CRF gene expression in the developing ovine brain.