Rosettes in Adrenal Development, Maintenance and Disease

点击翻译按钮获取中文摘要

The adrenal cortex continuously remodels in response to physiological cues, though the exact mechanisms that controls this remain less well understood. It is clear from our prior studies that during postnatal development, the adrenal cortex undergoes zonal transdifferentiation in which the zona Glomerulosa (zG) gives rise to the zona Fasciculata (zF). This process likely involves formation and resolution of multicellular rosettes via the adherens junction (AJ) complex. Although what role these structures play in the regulation of adrenal function as well as whether their dysregulation leads to disease has not been assessed. Given that primary aldosteronism (PA), the most common form of secondary hypertension, involves hyperplasic expansion of the zG, further study of the factors and/or signaling pathways involved in regulating zG development and maintenance is warranted. Our preliminary data, utilizing a b-catenin gain-of-function mouse model suggest that zG hyperplasia in PA is driven by a block in rosette resolution/transdifferentiation. In addition, this block involves the up-regulation of FGFR2 signaling which appears to be required for rosette formation during normal development. Further, we have found that rosettes act as a coordinating center for Ca2+ signaling, via the AJ complex, and subsequent aldosterone production. Based on our recent findings, it is increasing evident that further study of the role of AJs, rosettes and the signals that control them is warranted. Therefore, we propose the following: Aim 1. Determine how AJs and rosettes regulate postnatal zG development and function. Aim 2. Establish how FGFR2 signaling regulates postnatal zG development and function. Aim 3. Define the role of rosettes and β-Catenin in zG turnover and function in the adult. These studies seek to understand the regulatory mechanisms that control zG function during postnatal development and maintenance. The successful completion of these studies will provide critical insights into the mechanisms that govern zG homeostasis and the initiation and progression of PA, which may lead to new targeted therapies for this disease.