ELSEVIER MASSON
Wnt/Bcatenin signaling in adrenocortical stem/progenitor cells: Implications for adrenocortical carcinoma
La signalisation Wnt//Betacatenin dans les cellules souches et progénitrices de la corticosurrénale : implication dans le corticosurrénalome
A. Kimª, T .- J. Giordano b, R. Kuick℃, K. Sereckyd, G.D. Hammer a,d,e,*
a Cellular and Molecular Biology Training Program, University of Michigan, 109 Zina Pitcher Place, 1502 BSRB, Ann Arbor MI 48109-2200, United States
b Department of Pathology, University of Michigan, 109 Zina Pitcher Place, 1502 BSRB, Ann Arbor MI 48109-2200, United States
” Department of Pediatrics, University of Michigan, 109 Zina Pitcher Place, 1502 BSRB, Ann Arbor MI 48109-2200, United States
d Department of Molecular and Integrative Physiology, University of Michigan, 109 Zina Pitcher Place, 1502 BSRB, Ann Arbor MI 48109-2200, United States
e Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, 109 Zina Pitcher Place, 1502 BSRB, Ann Arbor MI 48109-2200, United States
Available online 14 March 2009
The long range objective of my laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland in health and disease. Recent efforts examine the hypothesis that Wnt/ßcatenin signaling maintains the functional capacity of the adrenal cortex though the regulation of undifferentiated adreno- cortical cell fate. Dysregulation of this system is predicted to result in abnormal adrenocortical growth and/or differentiation. Using cellular systems, mouse models together with genomic approaches with mouse and human adrenocortical carcinoma (ACC) samples, we aim to characterize the stem/progenitor cells of the adrenal cortex and uncover the mechanisms by which these cells are regulated by Wnt/Bcatenin signaling in normal adrenal growth maintenance and cancer.
In the adrenal cortex, Wnt/Bcatenin signaling is restricted to the subcapsular region. While these subcapsular undifferen-
tiated adrenocortical cells are known to migrate centripetally into the cortical zones of the gland to populate the three zones of the adrenal cortex, the molecular mechanism underlying role of these cells in tissue homeostasis is poorly under- stood. We present data that support a role of Wnt/Bcatenin signaling in the self-renewal and multipotent properties of these adrenocortical cells in vivo. We also characterize mech- anisms by which loss and gain of Wnt/Bcatenin signaling participate in the development of adrenal failure and ACC, respectively. ACC is an incredibly rare and routinely fatal dis- ease with few effective treatments. Understanding the role of Wnt/Bcatenin signaling in adrenocortical cell fate will lay essen- tial groundwork for future therapies that target this pathway and downstream genes that are found in the course of these studies to participate in adrenocortical stem/progenitor cell biol- ogy.
* Corresponding author. E-mail address: ghammer@med.umich.edu (A. Kim).