Regulation of corticotropin-releasing hormone (CRH) transcription and CRH mRNA stability by glucocorticoids

Abstract

1. The increases in corticotropin-releasing hormone (CRH) mRNA following long-term adrenalectomy are associated with low levels of CRH gene transcription, suggesting that glucocorticoids regulate CRH mRNA at the posttranscriptional level. In this study we determined the time course of transcriptional activation after early adrenalectomy by intronic in situ hybridization, and evaluated the effects of glucocorticoids on CRH mRNA stability. 2. Plasma corticosterone was undetectable 3 h after adrenalectomy, but CRH hnRNA increased only by 12 h, and remained elevated for the next 72 h. CRH mRNA increased 18 h after adrenalectomy and reached a plateau lasting from 2 to 6 days, despite very low CRH hnRNA levels. 3. Assessment of CRH mRNA stability, by incubation of slide-mounted hypothalamic sections in an intracellular-like medium at 37 degrees C, prior to measuring CRH mRNA levels by in situ hybridization, revealed a half-life (t1/2) of 11.5 min in sham-operated rats, and a slower decrease adrenalectomized rats (t1/2--26.3 min). Corticosterone administration for 3 days markedly decreased CRH mRNA t1/2 in both sham-operated and adrenalectomized rats (6.5 and 5.0 min, respectively). 4. The data show that adrenalectomy causes transient increases in CRH mRNA transcription, followed by decreases in the rate of CRH mRNA degradation. This suggests that glucocorticoids regulate CRH mRNA at two sites, by inhibiting transcription and by decreasing mRNA stability.