Deletion of tyrosine hydroxylase gene reveals functional interdependence of adrenocortical and chromaffin cell system in vivo

Catecholamines are produced in the medulla of the adrenal gland and may par ticipate in the intraglandular regulation of its cortex We analyzed the adr enal structure and function of albino tyrosine hydroxylase-null (TH-null) m ice that are deficient in adrenal catecholamine production. Adrenal catecho lamines were markedly reduced, and catecholamine histofluorescence was abro gated in 15-day-old TH-null mice. Chromaffin cell structure was strikingly altered at the ultrastructural level with a depletion of chromaffin vesicle s and an increase in rough endoplasmic reticulum compared with wild-type mi ce. Remaining chromaffin vesicles lined up proximally to the cell membrane in preparation for exocytosis providing a "string-of-pearls" appearance. Th ere was a 5-fold increase in the expression of proenkephalin mRNA(502.8 +/- 142% vs. 100 +/- 17.5%, P = 0.016) and a 2-fold increase in the expression of neuropeptide Y(213.4 +/- 41.2% vs. 100 +/- 59.9%, P = 0.014) in the TH- null animals as determined by quantitative TaqMan (Perkin-Elmer) PCR. Accor dingly, immunofluorescence for met-enkephalin and neuropeptide tyrosine in these animals was strongly enhanced. The expression of phenylethanolamine I V-methyl transferase and chromogranin B mRNA was similar in TH-null and wil d-type mice. In TH-null mice, adrenocortical cells were characterized by an increase in liposomes and by tubular mitochondria with reduced internal me mbranes, suggesting a hypofunctional state of these steroid-producing cells . In accordance with these findings, plasma corticosterone levels were decr eased. plasma ACTH levels were not significantly different in TH-null mice. In conclusion, both the adrenomedullary and adrenocortical systems demonst rate structural and functional changes in catecholamine deficient TH-null m ice, underscoring the great importance of the functional interdependence of these systems in vivo.