Abrogation of FGFR signaling blocks β-catenin–induced adrenocortical hyperplasia and aldosterone production
Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A. Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S. Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q. Barrett, Diana L. Carlone, Kleiton Silva Borges, David T. Breault
Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A. Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S. Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q. Barrett, Diana L. Carlone, Kleiton Silva Borges, David T. Breault
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Research Article Cardiology Endocrinology

Abrogation of FGFR signaling blocks β-catenin–induced adrenocortical hyperplasia and aldosterone production

Abstract

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors critical for organogenesis and tissue maintenance, including in the adrenal gland. Here we delineate the role of FGFR2 in the morphogenesis, maintenance, and function of the adrenal cortex with a focus on the zona glomerulosa (zG). zG-specific Fgfr2 deletion (Fgfr2-cKO) resulted in impaired zG cell identity, proliferation, and transdifferentiation into zona fasciculata (zF) cells during postnatal development. In adult mice, induced deletion of Fgfr2 led to loss of mature zG cell identity, highlighting the importance of FGFR2 for the maintenance of a differentiated zG state. Strikingly, Fgfr2-cKO was sufficient to fully abrogate β-catenin–induced zG hyperplasia and to reduce aldosterone levels. Finally, short-term treatment with pan-FGFR small molecule inhibitors suppressed aldosterone production in both WT and β-catenin gain-of-function mice. These results demonstrate a critical role for FGFR signaling in adrenal morphogenesis, maintenance, and function and suggest that targeting FGFR signaling may benefit patients with aldosterone excess and/or adrenal hyperplasia.

Authors

Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A. Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S. Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q. Barrett, Diana L. Carlone, Kleiton Silva Borges, David T. Breault

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Figure 1

Tissue-specific Fgfr2 KO (Fgfr2 cKO) impairs zG cell identity and transdifferentiation.

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Tissue-specific Fgfr2 KO (Fgfr2 cKO) impairs zG cell identity and transd...
(A) Lineage-tracing by immunofluorescence for GFP+ cells in adrenal glands from 20-week-old female Fgfr2-cKO and control mice (Ctrl, ASCre/+ R26RmTmG/+). White dashed box demarcates region enlarged to the right. (B) Quantification of GFP+ cells within the zG and zF from female Ctrl and Fgfr2-cKO (cKO) mice (20–24 weeks). One-way ANOVA with post hoc Tukey’s test, ****P < 0.0001, n = 5, 6 mice, respectively. (C) Representative images of DAB2 immunostaining in adrenal glands from adult female Ctrl and Fgfr2-cKO mice (10–24 weeks). (D) Quantification of DAB2+ cells in female Ctrl and Fgfr2-cKO mice (10–24 weeks). Student’s t test, ****P < 0.0001, n = 6, 5, respectively. (E) Representative pictures of Aldosterone Synthase (AS; Cyp11b2) immunostaining in adrenal glands from female Ctrl and Fgfr2-cKO mice (10–24 weeks). (F) Quantification of AS+ cells in female Ctrl and Fgfr2-cKO mice (10–24 weeks). Student’s t test, *P < 0.05, n = 7, 5, respectively. (G) Representative images of coimmunostaining of GFP (green) and Ki67 (magenta) in Ctrl and Fgfr2-cKO adrenal glands from female mice (20–24 weeks). White arrowheads point to GFP and Ki67–copositive cells. (H) Quantification of GFP and Ki67–copositive cells as a proportion of total GFP+ cells in the zG and zF of female Ctrl and Fgfr2-cKO mice (20–24 weeks). Student’s t test, *P < 0.05. n = 5, 3 mice, respectively. Scale bars: 50 μm. DAPI (blue), nuclei. Dashed white lines correspond to the zG-zF boundary.