Toying with fate: Redirecting the differentiation of adrenocortical progenitor cells into gonadal-like tissue

• GDX-induced adrenocortical neoplasia is a model of altered steroidogenic cell fate.
• Genetic and epigenetic changes accompany GDX-induced adrenocortical neoplasia.
• GATA4 is crucial for the differentiation of gonadal-like cells in this model.
• GATA6 limits gonadal-like differentiation in the adrenal cortex.
• GATA6 is essential for proper development of the adrenal X-zone.

Cell fate decisions are integral to zonation and remodeling of the adrenal cortex. Animal models exhibiting ectopic differentiation of gonadal-like cells in the adrenal cortex can shed light on the molecular mechanisms regulating steroidogenic cell fate. In one such model, prepubertal gonadectomy (GDX) of mice triggers the formation of adrenocortical neoplasms that resemble luteinized ovarian stroma. Transcriptomic analysis and genome-wide DNA methylation mapping have identified genetic and epigenetic markers of GDX-induced adrenocortical neoplasia. Members of the GATA transcription factor family have emerged as key regulators of cell fate in this model. Expression of Gata4 is pivotal for the accumulation of gonadal-like cells in the adrenal glands of gonadectomized mice, whereas expression of Gata6 limits the spontaneous and GDX-induced differentiation of gonadal-like cells in the adrenal cortex. Additionally, Gata6 is essential for proper development of the adrenal X-zone, a layer analogous to the fetal zone of the human adrenal cortex. The relevance of these observations to developmental signaling pathways in the adrenal cortex, to other animal models of altered adrenocortical cell fate, and to human diseases is discussed.

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