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

Abstract

Catecholamines are produced in the medulla of the adrenal gland and may participate in the intraglandular regulation of its cortex. We analyzed the adrenal structure and function of albino tyrosine hydroxylase-null (TH-null) mice that are deficient in adrenal catecholamine production. Adrenal catecholamines were markedly reduced, and catecholamine histofluorescence was abrogated in 15-day-old TH-null mice. Chromaffin cell structure was strikingly altered at the ultrastructural level with a depletion of chromaffin vesicles and an increase in rough endoplasmic reticulum compared with wild-type mice. Remaining chromaffin vesicles lined up proximally to the cell membrane in preparation for exocytosis providing a ''string-ofpearls'' appearance. There 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. Accordingly, immunofluorescence for met-enkephalin and neuropeptide tyrosine in these animals was strongly enhanced. The expression of phenylethanolamine N-methyl transferase and chromogranin B mRNA was similar in TH-null and wild-type mice. In TH-null mice, adrenocortical cells were characterized by an increase in liposomes and by tubular mitochondria with reduced internal membranes, suggesting a hypofunctional state of these steroid-producing cells. In accordance with these findings, plasma corticosterone levels were decreased. Plasma ACTH levels were not significantly different in TH-null mice. In conclusion, both the adrenomedullary and adrenocortical systems demonstrate structural and functional changes in catecholaminedeficient TH-null mice, underscoring the great importance of the functional interdependence of these systems in vivo.

Biochemical Characterization and Immunocytochemical Localization of EM66, a Novel Peptide Derived from Secretogranin II, in the Rat Pituitary and Adrenal Glands

“…Several reports have previously shown the existence of rays and islets of chromaffin cells in the adrenal cortex (Palacios and Lafarga 1975;Gallo-Payet et al 1987;Bornstein et al 1991;Perraudin et al 1993;Berka et al 1996). The present data indicate that these extramedullary adrenochromaffin cells also contain EM66-IR, suggesting that EM66 could play a role in the paracrine communication that occurs between chromaffin and steroidogenic cells in the adrenal gland (Bornstein and Ehrhart-Bornstein 1992;Ehrhart-Bornstein et al 1998;Bornstein et al 2000;Delarue et al 2001).…”

Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog

“…Although exogenous glucocorticoids are known to elevate BP (42) and glucocorticoid abnormalities are implicated in the pathogenesis of human hypertension (43), the mechanism underlying glucocorticoid excess in Chga -/-mice is uncertain at this time. However, several observations suggest that alterations in chromaffin cell transmitters can have profound consequences for adjacent adrenocortical cells (44)(45)(46).…”

Expression of the Epithelial Marker E-Cadherin by Thyroid C Cells and Their Precursors During Murine Development

“…Tyrosine hydroxylase, which is a rate-limiting enzyme for catecholamine synthesis, is expressed by some neural crest-derived cells (Fauquet and Ziller 1989). Instead, in the mouse, the cells that express tyrosine hydroxylase and enkephalins are the adrenal chromaffin cells, which are derived from the neural crest cells (Bornstein et al 2000;Huber et al 2002).…”