Beta-Catenin Causes Adrenal Hyperplasia by Blocking Zonal Transdifferentiation
Emanuele Pignatti,
Sining Leng,
Yixing Yuchi,
Kleiton S. Borges,
Nick A. Guagliardo,
Manasvi S. Shah,
Gerard Ruiz-Babot,
Dulanjalee Kariyawasam,
Makoto Mark Taketo,
Ji Miao,
Paula Q. Barrett,
Diana L. Carlone,
David T. Breault
Affiliations
Emanuele Pignatti
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Sining Leng
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA
Yixing Yuchi
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Kleiton S. Borges
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Nick A. Guagliardo
Department of Pharmacology, University of Virginia, Charlottesville, VA 22947, USA
Manasvi S. Shah
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Gerard Ruiz-Babot
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Dulanjalee Kariyawasam
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Makoto Mark Taketo
Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8506, Japan
Ji Miao
Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Paula Q. Barrett
Department of Pharmacology, University of Virginia, Charlottesville, VA 22947, USA
Diana L. Carlone
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
David T. Breault
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; Corresponding author
Summary: 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. : Using the adrenal cortex as a model for slow-cycling tissues, Pignatti et al. show that activation of the canonical Wnt/β-catenin pathway leads to tissue hyperplasia by blocking cellular differentiation/cell-fate commitment, independent of its effects on cellular proliferation. Keywords: hyperplasia, Wnt signaling, beta-catenin, adrenal cortex, cell transdifferentiation
