Mechanisms Leading to Adrenal Zonation

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DESCRIPTION (provided by applicant): BACKGROUND: The human adrenal cortex acts as a compound endocrine gland that secretes both mineralocorticoids and glucocorticoids. These steroids arise from distinct zones of the adrenal cortex that have both morphologic and biochemical differences. Neither the origin of the stem cells of the cortical zones nor the mechanisms leading to the zone-specific production of steroids is clearly defined. The functional zonation of the adrenal cortex can be traced to the zone-specific expression of the enzymes involved in steroid biosynthesis. This is particularly true for aldosterone synthase (CYP11B2), 11 beta-hydroxylase (CYP11B1) and 17alpha-hydroxylase (CYP17). AIMS: The experiments proposed in Specific Aim One will extend the applicants ongoing collaborative project that has defined the regulatory elements in the 5'-flanking region of the (CYP11B2) and 11beta-hydroxylase (CYP11B1) genes. These studies will complete the definition of the transacting factors responsible for glomerulosa-specific expression and fasciculata repression of CYP11B2. Focus will be placed on the role of the nuclear receptor, NURR1 (NR4A2), which stimulates CYP11B2 promoter activity, which is up-regulated by angiotensin II and is expressed primarily in the zona glomerulosa. Specific Aim Two will determine the mechanisms responsible for the lack of CYP17 seen in the glomerulosa. Preliminary studies indicate that this results from multiple mechanisms including angiotensin II increased AP-1 transcription factors and WNT signaling. The WNT downstream factors responsible for CYP17 repression and the mechanisms of AP-1 repression of CYP17 transcription will be defined. Specific Aim Three will extend our ongoing adrenal cell culture studies to the in vivo situation using bacterial artificial chromosome (BAC) transgenesis to target the zona glomerulosa with an inhibitor of NURR1. The murine adrenal, like the human adrenal, limits expression of CYP11B2 to the zona glomerulosa making it an excellent model to define the factors regulating aldosterone production. We will also use this strategy to produce a glomerulosa-CRE mouse that will be an important tool for further study of genes that may regulate glomerulosa function. SIGNIFICANCE: Hyperaldosteronism results from the disruption of zonation, and particularly aberrant CYP11B2 expression, in nodular hyperplasia and aldosterone-producing adenomas. The proposed studies will provide a detailed understanding of the molecular mechanisms regulating CYP11B2 expression within the adrenal and should provide insight into the diseases associated with aberrant expression.