Regulation of zonation and homeostasis in the adrenal cortex

Abstract

The adult adrenal cortex is organized into concentric zones, each specialized to produce distinct steroid hormones. Cellular composition of the cortex is highly dynamic and subject to diverse signaling controls. Cortical homeostasis and regeneration rely on centripetal migration of steroidogenic cells from the outer to the inner cortex, which is accompanied by direct conversion of zona glomerulosa (zG) into zona fasciculata (zF) cells. Given the important impact of tissue structure and growth on steroidogenic function, it is essential to understand the mechanisms governing adrenal zonation and homeostasis. Towards this end, we review the distinctions between each zone by highlighting their morphological and ultra-structural features, discuss key signaling pathways influencing zonal identity, and evaluate current evidence for long-term self-renewing stem cells in the adult cortex. Finally, we review data supporting zG-to-zF transdifferentiation/direct conversion as a major mechanism of adult cortical renewal.

Keywords: ACTH; Adrenal cortex; Stem cell; Transdifferentiation; Wnt/β-catenin; Zonation.

Figure 1. Cyp11b2 is expressed in a patchy fashion in the zG

Immunofluorescent staining of paraffin sections from a wild-type adrenal cortex. The expression pattern of Cyp11b2 is restricted to the putative zG region, marked by β-catenin. However, not all β-catenin positive cells also express Cyp11b2, indicating that Wnt/β-catenin signaling is likely necessary but not sufficient for the synthesis of aldosterone. Insets are magnified details of the larger image. Scale bar: 100μm.

Figure 2. Cellular mechanisms underlying adrenocortical renewal in the adult

A, Schematic showing location of proposed markers for clonogenic capsular cells (Gli1⁺, WT1⁺, Tcf21⁺; grey with brown nuclei), putative TA progenitors (Shh⁺; yellow), aldosterone-producing zG cells (Cyp11b2⁺; purple), non-aldosterone-producing zG cells (Cyp11b2⁻, can be identified with pan-zG markers such as At1r, β-catenin; grey with red nuclei), and zF cells (Cyp11b1⁺; blue). Red nuclei denote Sf1⁺ cells. B, Left panel, schematic showing progression of lineage marking in AS-Cre/+; R26R-mTmG mice during normal tissue maintenance. The Cyp11b2⁺ lineage gives rise to the entire cortex through transdifferentiation/direct conversion and centripetal migration. Right panel, schematic showing disruption of the zG following Sf1 deletion in AS-Cre/+; Sf1 fl/fl; R26R-mTmG mice. In these mice Cyp11b2⁻ cells give rise to a normal zF. Green cells denote lineage-marked Cyp11b2⁺ cells and their descendants and red nuclei denote Sf1⁺ cells. m, medulla.

Figure 3. Cyp11b2⁺ lineage contributes to the entire zG and the majority of the zF by ~3 months of age

Representative confocal images showing co-immunofluorescent staining of paraffin sections of adrenals from female AS-Cre/+; R26R-mTmG mice. The entire zG and the majority of the zF became labeled within 3 months. A, GFP expression completely overlaps with β-catenin staining in the zG. B, Sf1 staining reveals all steroidogenic cells in the zG and the majority of cells in the zF are marked by GFP. Insets are magnified details of the larger image. Scale bar: 100μm.