Cell Loss and Autophagy in the Extra‐Adrenal Chromaffin Organ of Zuckerkandl are Regulated by Glucocorticoid Signalling

Andreas Schober,Björn Hartleben,Ralf Kinscherf,Tobias B Huber,Rosanna Parlato,Klaus Unsicker,Katrin Huber,Günther Schütz

doi:10.1111/j.1365-2826.2012.02367.x

Abstract

Neuroendocrine chromaffin cells exist in both intra- and extra-adrenal locations; the organ of Zuckerkandl (OZ) constitutes the largest accumulation of extra-adrenal chromaffin tissue in mammals. The OZ disappears postnatally by modes that are still enigmatic but can be maintained by treatment with glucocorticoids (GC). Whether the response to GC reflects a pharmacological or a physiological role of GC has not been clarified. Using mice with a conditional deletion of the GC-receptor (GR) gene restricted to cells expressing the dopamine β-hydroxylase (DBH) gene [GRfl/fl; DBHCre abbreviated (GRDBHCre)], we now present the first evidence for a physiological role of GC signalling in the postnatal maintenance of the OZ: postnatal losses of OZ chromaffin cells in GRDBHCre mice are doubled compared to wild-type littermates. We find that postnatal cell loss in the OZ starts at birth and is accompanied by autophagy. Electron microscopy reveals autophagic vacuoles and autophagolysosomes in chromaffin cells. Autophagy in OZ extra-adrenal chromaffin cells is confirmed by showing accumulation of p62 protein, which occurs, when autophagy is blocked by deleting the Atg5 gene (Atg5DBHCre mice). Cathepsin-D, a lysosomal marker, is expressed in cells that surround chromaffin cells and are positive for the macrophage marker BM8. Macrophages are relatively more abundant in mice lacking the GR, indicating more robust elimination of degenerating chromaffin cells in GRDBHCre mice than in wild-type littermates. In summary, our results indicate that extra-adrenal chromaffin cells in the OZ show signs of autophagy, which accompany their postnatal numerical decline, a process that is controlled by GR signalling.

Highlights

Neuroendocrine chromaffin cells exist in both intra- and extra-adrenal locations; the organ of Zuckerkandl (OZ) constitutes the largest accumulation of extra-adrenal chromaffin tissue in mammals
Localisation of OZ Emil Zuckerkandl, who discovered the OZ (‘Nebenorgane des Sympathicus’ in his terminology), described its localisation in of the coeliac and superior mesenteric sympathetic ganglia (Fig. 2), its precise localisation requires methods to unequivocally distinguish between neuroendocrine chromaffin cells and sympathetic neurones
We investigated the impact of a deletion of the GR gene (GRDBHCre) on the postnatal development of the OZ

Summary

Introduction

Neuroendocrine chromaffin cells exist in both intra- and extra-adrenal locations; the organ of Zuckerkandl (OZ) constitutes the largest accumulation of extra-adrenal chromaffin tissue in mammals. Our results indicate that extra-adrenal chromaffin cells in the OZ show signs of autophagy, which accompany their postnatal numerical decline, a process that is controlled by GR signalling. Chromaffin cells are neuroendocrine cells derived from the neural crest [1,2] They populate the adrenal medulla and extra-adrenal sympathetic paraganglia. The close spatial association of adrenal medullary chromaffin cells and steroid hormone producing cells of the adrenal cortex has always fostered speculation concerning a role of glucocorticoids (GC) in the determination and differentiation of the chromaffin cell phenotype. Suppression of the neuronal differentiation in isolated embryonic and early postnatal cells cultured from sympathetic ganglia and adrenal medulla by GC [21,22] generated the hypothesis that GC signalling might be important for the specification of the chromaffin as opposed to the neuronal phenotype. With regard to extra-adrenal chromaffin tissues, numerous studies have shown that application of GC causes hyperplasia of chromaffin cells [3,25,26,27,28,29]

Methods

Results

Conclusion