Beta-Catenin Causes Adrenal Hyperplasia by Blocking Zonal Transdifferentiation
Authors: Kleiton S Borges
Ji Miao
Yixing Yuchi
David T Breault
Gerard Ruiz-Babot
Manasvi S Shah
Emanuele Pignatti
Paula Q Barrett
Nick A Guagliardo
Sining Leng
Dulanjalee Kariyawasam
Makoto Mark Taketo
Diana L Carlone
Journal: Cell reports (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Wnt signaling; adrenal cortex; beta-catenin; cell transdifferentiation; hyperplasia.
Affiliations: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA., Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA., Department of Pharmacology, University of Virginia, Charlottesville, VA 22947, USA., Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8506, Japan., Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA., Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: .

Abstract:  Activating mutations in the canonical Wnt/β-catenin pathway are key drivers of hyperplasia, the gateway for tumor development. In a wide range of tissues, this occurs primarily through enhanced effects on cellular proliferation. Whether additional mechanisms contribute to β-catenin-driven hyperplasia remains unknown. The adrenal cortex is an ideal system in which to explore this question, as it undergoes hyperplasia following somatic β-catenin gain-of-function (βcat-GOF) mutations. Targeting βcat-GOF to zona Glomerulosa (zG) cells leads to a progressive hyperplastic expansion in the absence of increased proliferation. Instead, we find that hyperplasia results from a functional block in the ability of zG cells to transdifferentiate into zona Fasciculata (zF) cells. Mechanistically, zG cells demonstrate an upregulation of Pde2a, an inhibitor of zF-specific cAMP/PKA signaling. Hyperplasia is further exacerbated by trophic factor stimulation leading to organomegaly. Together, these data indicate that β-catenin drives adrenal hyperplasia through both proliferation-dependent and -independent mechanisms. 

Retracted: No

PubPeer comments:
 In this study, only circumstantial evidence is presented that Pde2a is involved in determining the adrenal phenotype of beta-cat GOF mice. Pde2a protein levels are not shown and at the very least functional experiments in an adrenal cell line should be made to confirm beta-catenin upregulation of Pde2a . Furthermore, the authors could have used Pde2a specific inhibitors (*e.g*. BAY-60-7550) or genetic rescue by crossing with *Pde2a *+ - mice (homozygote KO not being viable) to show that Pde2a really has a role in determining the adrenal phenotype of beta-cat GOF mice. , 
 In this paper, compelling data are presented which confute the study by Berthon *et al. *(*Hum. Mol. Genet.* 23: 889, 2014) pretending that beta-catenin directly regulates aldosterone production in the adrenal *zona glomerulosa*. ,