Contrasting Functions of Notch Signaling In Normal and Pathogenic Adrenal Biology.

Abstract

Cell-cell communication is essential for proper development and homeostasis, the dysregulation of which can manifest in developmental defects and/or cancer. The Notch signaling pathway is an evolutionarily conserved pathway that has been implicated in many aspects of these processes. The adrenal glands are endocrine organs that mediate the mammalian stress response and are comprised of the embryological and functionally distinct cortex, which secretes steroid hormones, and medulla, which secretes catecholamine hormones. Benign tumors of the adrenal cortex, adrenocortical adenomas (ACA), are common while adrenocortical carcinomas (ACC) present at much lower frequency but with an extremely poor prognosis. The Notch ligand Jag1 is upregulated in ACCs compared to ACAs and normal adrenals concomitant with upregulations of Notch receptors and target genes. The expression of Jag1 correlates with markers of proliferation and with late stage, aggressive ACC. Upregulated Jag1 mediates a non-cell autonomous effect on cell proliferation through the activation of canonical Notch signaling. In contrast, Notch signaling has no apparent role in the normal adrenal cortex. On the contrary, Notch ligands, receptors, and target genes are expressed in chromaffin cells of the adrenal medulla. Inhibition of canonical Notch signaling in chromaffin cells results in an upregulation of catecholamine-synthesizing enzyme TH while constitutive activation of Notch signaling reduces the expression of the epinehprine-synthesizing enzyme PNMT in chromaffin cells. This thesis interrogates the contrasting roles of Notch signaling in the molecular biology of the pathogenic adrenal cortex and normal adrenal medulla.