Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

Abstract

Corticotropin-releasing hormone (CRH) is both a main regulator of the hypothalamic-pituitaryadrenocortical axis and the autonomic nervous system. CRH receptor type 1 (CRHR1)-deficient mice demonstrate alterations in behavior, impaired stress responses with adrenocortical insufficiency and aberrant neuroendocrine development, but the adrenal medulla has not been analyzed in these animals. Therefore we studied the production of adrenal catecholamines, expression of the enzyme responsible for catecholamine biosynthesis neuropeptides and the ultrastructure of chromaffin cells in CRHR1 null mice. In addition we examined whether treatment of CRHR1 null mice with adrenocorticotropic hormone (ACTH) could restore function of the adrenal medulla. CRHR1 null mice received saline or ACTH, and wildtype or heterozygous mice injected with saline served as controls. Adrenal epinephrine levels in saline-treated CRHR1 null mice were 44% those of controls (P Ͻ0.001), and the phenylethanolamine N-methyltransferase (PNMT) mRNA levels in CRHR1 null mice were only 25% of controls (P Ͻ0.001). ACTH treatment increased epinephrine and PNMT mRNA level in CRHR1 null mice but failed to restore them to normal levels. Proenkephalin mRNA in both saline-and ACTH-treated CRHR1 null mice were higher than in control animals (215.8% P Ͻ0.05, 268.9% P Ͻ0.01) whereas expression of neuropeptide Y and chromogranin B did not differ. On the ultrastructural level, chromaffin cells in saline-treated CRHR1 null mice exhibited a marked depletion in epinephrine-storing secretory granules that was not completely normalized by ACTH-treatment. In conclusion, CRHR1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine biosynthesis. Molecular Psychiatry (2002) 7, 967-974.

Gene Expression of Phenylethanolamine N-Methyltransferase in Corticotropin-Releasing Hormone Knockout Mice During Stress Exposure

“…In the CRH-R1 receptor-deficient mice an impairment of both, adrenocortical and adrenomedullary function was found. Epinephrine release and the PNMT gene expression were significantly reduced in AM of these animals (Yoshida-Hiroi et al, 2002). Similarly, we found an impairment of the PNMT mRNA levels and epinephrine release in CRH knockout mice under stress conditions.…”

Expression of Ovary-Specific Acidic Protein in Steroidogenic Tissues: A Possible Role in Steroidogenesis

“…For example, ACTH, the principal positive regulator of adrenal steroidogenesis, induces an increase in mitochondrial abundance in adult human adrenocortical cells (18). In contrast, mice lacking CRH receptor-1 display a decrease in the amount of mitochondria in adrenocortical cells, consistent with decreased corticosterone production in these animals (19). Thus, the inhibition of 8-Br-cAMP-stimulated progesterone production in Y-1 cells transfected with OSAP siRNA may be secondary to the reduced cellular mitochondrial content, suggesting a role for OSAP in maintaining mitochondrial abundance.…”

The corticotropin-releasing factor (CRF) family of peptides as local modulators of adrenal function

“…The function of the adrenal medulla of Crf 1 -/-and Crf -/-mice is similarly impaired. Thus, basal epinephrine levels in Crf 1 -/-mice are less than 50% those of WT littermates, and PNMT mRNA levels in Crf 1 -/-mice are only 25% the level of their WT controls [170]. Histological examination revealed that chromaffin cells in Crf 1 -/-mice exhibit marked depletion in epinephrine-storing secretory granules, which was not completely normalized by ACTH treatment, suggesting that CRF 1 is required for normal chromaffin cell structure and function and that deletion of this gene is associated with a significant impairment of epinephrine biosynthesis.…”