2B or Not 2B: Capsular Wnt Activates Wnt-High Signaling to Maintain Adrenal Glomerulosa Identity
dc.contributor.author | Little III, Donald | |
dc.date.accessioned | 2022-01-19T15:26:39Z | |
dc.date.available | 2022-01-19T15:26:39Z | |
dc.date.issued | 2021 | |
dc.date.submitted | 2021 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/171405 | |
dc.description.abstract | The adrenal glands are endocrine organs that produce steroid hormones essential for life. Steroidogenesis occurs in the adrenal cortex, a highly regenerative tissue that is organized in concentric zones of cells surrounded by a mesenchymal capsule. Diseases of the adrenal cortex include hypo-/hyperplasia, dysfunctional steroid hormone production, and carcinoma. Adrenocortical carcinoma (ACC) is a rare but highly metastatic malignancy that poses a high risk of recurrence and for which successful targeted therapy options are lacking. Therefore, there is great need for understanding the basic underlying cellular and molecular mechanisms that are involved in ACC and other adrenal diseases. Long-term retained adrenocortical progenitor cells reside in the subcapsular zona glomerulosa (zG). The adrenal zG is a critical compartment of these undifferentiated progenitor cells as well as differentiated cells that produce aldosterone, an essential steroid hormone involved in physiological salt and water balance, that centripetally differentiate to replenish glucocorticoid-producing cells of the inner zona fasciculata (zF). Both progenitor and aldosterone-producing cell populations respond to Wnt/Beta-catenin signaling, a conserved paracrine pathway necessary for proper adrenocortical development and homeostasis. Wnt/Beta-catenin signaling is altered in 40% of ACCs and plays a role in several other adrenocortical diseases. Through our work, we have identified a capsular Wnt ligand that functions to activate and maintain Wnt-high activity in the adrenal cortex that is necessary for zG cell identity and proper functional capacity. The focus of this dissertation is to define the role this capsular Wnt ligand, WNT2B, in adrenocortical Wnt/Beta-catenin signaling and to determine the consequences of its loss on adrenocortical homeostasis. Here, we show that human patients with WNT2B loss, who exhibit chronic congenital diarrhea and subsequent hypovolemia, also have hypoaldosteronism that is compensated by excessive activation of the renin-angiotensin-aldosterone system (RAAS). To understand the mechanism by which WNT2B regulates zG cell aldosterone production, we developed a global Wnt2b knockout mouse model that exhibits near complete zG loss, indicating the necessity of WNT2B for proper zG development. Moreover, mice with conditional Wnt2b loss in adulthood have decreased adrenocortical cell proliferation and expression of progenitor cell markers, supporting a role for Wnt/Beta-catenin signaling in progenitor cell maintenance. Wnt2b-deficient mice also exhibit dampened Wnt-high activity in the adrenal zG. Finally, mice lacking Wnt2b exhibit downregulation of Cyp11b2, the terminal enzyme in aldosterone synthesis, but have comparable plasma aldosterone levels to controls. We then show that Wnt2b loss results in elevated plasma renin, which acts to compensate for the reduced steroidogenic capacity of differentiated zG cells of the adrenal cortex. Taken together, our studies illuminate the role of a newly discovered adrenal WNT ligand essential for the growth, maintenance, and physiological function of the adrenal zG. Our work highlights the underlying mechanisms of an adrenal defect in patients with LOF WNT2B mutations which we hope will inform our understanding and treatment of their disease as well as the molecular underpinnings of Wnt-active ACC. | |
dc.language.iso | en_US | |
dc.subject | Adrenal cortex | |
dc.subject | Wnt signaling | |
dc.subject | Endocrinology | |
dc.title | 2B or Not 2B: Capsular Wnt Activates Wnt-High Signaling to Maintain Adrenal Glomerulosa Identity | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Cancer Biology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Hammer, Gary D | |
dc.contributor.committeemember | Fearon, Eric R | |
dc.contributor.committeemember | Lombard, David | |
dc.contributor.committeemember | Rainey, William | |
dc.contributor.committeemember | Spence, Jason | |
dc.subject.hlbsecondlevel | Molecular, Cellular and Developmental Biology | |
dc.subject.hlbtoplevel | Science | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/171405/1/dwlittle_1.pdf | |
dc.identifier.doi | https://dx.doi.org/10.7302/3917 | |
dc.identifier.orcid | 0000-0001-5807-2400 | |
dc.working.doi | 10.7302/3917 | en |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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