The Role of Wnt Signaling in Adrenocortical Homeostasis.

[摘要] Wnt/beta-catenin signaling is critical for adrenal homeostasis. To elucidate how Wnt/beta-catenin signaling elicits homeostatic maintenance of the adrenal cortex, we characterized the identity of the adrenocortical Wnt-responsive population. We find that Wnt-responsive cells consist of both Sonic Hedgehog-producing (Shh) adrenocortical progenitors and differentiated, steroidogenic cells of the zona glomerulosa, but not the zona fasciculata. Additionally, Wnt-responsive cells are rarely actively proliferating.To determine potential direct inhibitory effects of beta-catenin signaling on zona fasciculata-associated steroidogenesis, we utilized the mouse ATCL7 adrenocortical cell line that serves as a model system of glucocorticoid-producing fasciculata cells. Stimulation of beta-catenin signaling caused decreased corticosterone release consistent with the observed reduced transcription of steroidogenic genes Cyp11a1, Cyp11b1, Star and Mc2r. Decreased steroidogenic gene expression was correlated with diminished Steroidogenic factor 1 (Nr5a1, Sf1) expression and decreased occupancy on steroidogenic promoters. Additionally, beta-catenin signaling suppressed the ability of Sf1 to transactivate steroidogenic promoters independent of changes in Sf1 expression level. To investigate Sf1-independent effects of beta-catenin on steroidogenesis, we utilized Affymetrix gene expression profiling of Wnt-responsive cells in vivo and in vitro. One candidate gene identified, Ccdc80, encodes a secreted protein with unknown signaling mechanisms. We report that Ccdc80 is a novel beta-catenin-regulated gene in adrenocortical cells. Treatment of adrenocortical cells with media containing secreted Ccdc80 partially phenocopies beta-catenin-induced suppression of steroidogenesis, through an Sf1-independent mechanism. The data presented in this thesis reveal multiple mechanisms of beta-catenin-mediated suppression of steroidogenesis and suggests that Wnt/βcat signaling regulates adrenal homeostasis by inhibiting fasciculata differentiation in addition to promoting the undifferentiated state of progenitor cells.

[发布机构] University of Michigan

[效力级别] Molecular

[关键词] Wnt Signaling;Molecular;Cellular and Developmental Biology;Health Sciences;Cellular & Molecular Biology