title: GLI1+progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue.
abstract: As certain strains of mice age, hyperplastic lesions resembling gonadal tissue accumulate beneath the adrenal capsule. Gonadectomy (GDX) accelerates this heterotopic differentiation, resulting in the formation of wedge-shaped adrenocortical neoplasms that produce sex steroids. Stem/progenitor cells that reside in the adrenal capsule and retain properties of the adrenogonadal primordium are thought to be the source of this heterotopic tissue. Here, we demonstrate that GLI1+progenitors in the adrenal capsule give rise to gonadal-like cells that accumulate in the subcapsular region. A tamoxifen-inducible Cre driver (Gli1-creERT2) and two reporters (R26R-lacZ, R26R-confetti) were used to track the fate of GLI1+cells in the adrenal glands of B6D2F2 mice, a strain that develops both GDX-induced adrenocortical neoplasms and age-dependent subcapsular cell hyperplasia. In gonadectomized B6D2F2 mice GLI1+progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers. Pdgfra, a gene expressed in adrenocortical stromal cells, was upregulated in the GDX-induced neoplasms. In aged non-gonadectomized B6D2F2 mice GLI1+progenitors gave rise to patches of subcapsular cell hyperplasia. Treatment with GANT61, a small-molecule GLI antagonist, attenuated the upregulation of gonadal-like markers (Gata4, Amhr2, Foxl2) in response to GDX. These findings support the premise that GLI1+progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic tissue.
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA; Hochschule Mannheim - University of Applied Sciences, 68163 Mannheim, Germany.
authors: Julia
authors: J
authors: Dörner
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA; Hochschule Mannheim - University of Applied Sciences, 68163 Mannheim, Germany.
authors: Verena
authors: V
authors: Martinez Rodriguez
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA; Hochschule Mannheim - University of Applied Sciences, 68163 Mannheim, Germany.
authors: Ricarda
authors: R
authors: Ziegler
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA; Hochschule Mannheim - University of Applied Sciences, 68163 Mannheim, Germany.
authors: Theresa
authors: T
authors: Röhrig
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA.
authors: Rebecca S
authors: RS
authors: Cochran
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA; Hochschule Mannheim - University of Applied Sciences, 68163 Mannheim, Germany.
authors: Ronni M
authors: RM
authors: Götz
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA.
authors: Mark D
authors: MD
authors: Levin
authors: University of Helsinki and Helsinki University Central Hospital, Children's Hospital, 00290 Helsinki, Finland.
authors: Marjut
authors: M
authors: Pihlajoki
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA; University of Helsinki and Helsinki University Central Hospital, Children's Hospital, 00290 Helsinki, Finland.
authors: Markku
authors: M
authors: Heikinheimo
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110 USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110 USA. Electronic address: wilson_d@wustl.edu.
authors: David B
authors: DB
authors: Wilson
mesh_terms: D000311:Adrenal Glands / Q000166:cytology*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002828:Choristoma / Q000473:pathology*; D005260:Female; D006066:Gonads / Q000473:pathology* / Q000601:surgery; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013234:Stem Cells / Q000166:cytology*; D013256:Steroids / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C498520:Gli1 protein, mouse; D013256:Steroids; D000071676:Zinc Finger Protein GLI1; C045073:Cre recombinase; D019426:Integrases
keywords: Adrenal cortex; Gonadectomy; Gonadotropin; Lineage tracing; Orchiectomy; Ovariectomy