MOLECULAR MECHANISMS OF ADRENAL DEVELOPMENT

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Adrenal gland development is complex and poorly understood at the molecular level. In the prenatal period, there is massive growth of a fetal cortical zone, and in the postnatal period, the fetal cortex disappears and the definitive adult cortex develops. Adrenal ontogeny is a model for organ development, involving biological mechanisms as varied as cell growth and differentiation, cell migration and apoptosis. Our overarching hypothesis is that specifically regulated genes play definable roles at critical stages of adrenal development, and that these genes, through recognizable functional motifs, interact within a complex network of developmentally regulated genes. We further hypothesize that congenital abnormalities of adrenals may result from specific defects in these developmental pathways. Therefore, our broad objective for the proposal is to identify genes involved in adrenal cortical development, during the pre- and postnatal periods, and to characterize their structural and functional interactions. In order to achieve this objective, we will pursue the following Specific Aimes: (1) To identify and characterize genes differentially expressed during adrenal cortical development, including those involved in the (a) Development of the fetal adrenal cortex; and (b) Transition from fetal to adult cortex postpartum. (2) To characterize the developmental function of DAX1, the gene responsible, when mutated, for Adrenal Hypoplasia Congenita (AHC), including (a) Partners with DAX1; and (b) relationships between structure and function for the DAX1 protein. The results of these investigations will improve our understanding of the molecular mechanisms involved in normal adrenal cortical ontogeny. In addition, we will elucidate mechanisms and identify candidate genes for pathologic processes as varied as adrenal cortical aplasia, hypoplasia and tumorigenesis.