The developmental regulation of the adrenocorticotropic hormone-signaling pathway in the neonatal rat adrenal cortex

During neonatal development, the rat adrenal gland undergoes maturational changes essential for ex utero survival. These changes result in functionally mature adrenal glands characterized by their responsiveness to adrenocorticotropic hormone (ACTH) and by their increased secretion of glucocorticoids. To elucidate the developmental regulation of the ACTH-signaling pathway during the neonatal period, several intracellular factors were examined. Expression of the peripheral-type benzodiazepine receptor (PBR), which is required for cholesterol delivery to mitochondria, a prerequisite for steroidogenesis, closely parallels the advent of ACTH-induced corticosterone production. Additionally, expression of DAX-1, a gene transcriptional repressor required for adrenal organogenesis, decreases at later juvenile ages when ACTH-induced steroid production increases. These data suggest that ontogenic changes resulting in increased ACTH-sensitivity of developing rat adrenocortical cells occur at multiple loci in the signaling pathway.; Because ACTH is an important developmental stimulus that accelerates the appearance of functionally mature adrenal glands in neonatal rats, experiments were designed to determine whether maturation of the adrenal gland is maintained and mediated by increased PBR. ACTH increases PBR expression and steroidogenic capacity of developing rat adrenal glands. However, its effects are transient and only manifest when pups are exposed regularly to high plasma ACTH levels. ACTH, therefore, has significant, but reversible, effects on the development of adrenocortical function, possibly partly mediated by increased PBR expression.; To gain more insight into intracellular effects of chronic ACTH stimulation on rat adrenal gland development, DNA microarray technologies were used to identify ACTH-regulated genes. ACTH significantly upregulates many genes involved in cell signaling, gene transcription and cell growth, as well as others associated with inhibition of maximal steroid synthesis. Collectively, gene expression analysis indicates that ACTH is involved with nearly all aspects of adrenal cell function. It not only upregulates the steroidogenic capacity of immature adrenal cells by stimulating cell growth and differentiation, but also appears simultaneously to limit steroidogenesis by reducing cholesterol synthesis and transport. This may be a key adaptive feature of developing adrenal glands to prevent exposure of developing organs to cytotoxic glucocorticoid concentrations.