To investigate the role of TP53 in adrenocortical zonation through targeted disruption in Aldosterone Synthase (AS)-expressing adrenal cells during post-natal development, maintenance and regeneration

Abstract

The human adult adrenal cortex is composed of the zona glomerulosa (zG), zona fasciculata (zF), and zona reticularis (zR), which are responsible for production of mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. Starting shortly after birth, a rapid, dramatic remodeling of adrenal cortex structure takes place, with massive shrinkage of the gland due to apoptosis of the fetal zone and progressive differentiation of the definitive adrenocortical zones, which are the hallmark of the adult adrenal. Recently, through cell fate mapping and gene deletion studies using zG-specific Cre expression, Dr. Breault's team demonstrated that differentiated zG cells undergo lineage conversion into zF cells and that zG-specific Sf-1 deletion prevents such lineage conversion. These findings lead us to hypothesize that other genes may also be regulating this process. TP53 gene is a transcription factor and an important tumour suppressor that is inactivated in most cancers. The high incidence of pediatric adrenocortical tumors in children with germline TP53 mutations suggests that normal p53 function is required for the physiological process of postnatal fetal adrenal. Interestingly, TP53 mutation is not by itself sufficient to promote adrenocortical tumorigenesis but must cooperate with other genetic alterations, such as activation of Wnt/²-catenin. Wnt/²-catenin signaling is critical for adrenal homeostasis and the crosstalk between p53 and Wnt signaling pathways has been showed by previous studies. However, it has never been investigated in the context of adrenocortical zonation. Here, we hypothesize that targeted disruption of p53 in Aldosterone Synthase (AS)-expressing cells (zG specific) may lead to aberrant B-catenin activity affecting adrenocortical homeostasis, zonation, regenerative capacity and tumor susceptibility. To test this hypothesis, we will explore the role of p53 in mouse adrenocortical zonation through its targeted disruption in Aldosterone Synthase (AS)-expressing adrenal cells during post-natal development, tissue maintenance and regeneration. This approach could provide essential new insight into adrenal development and tumor formation.