GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue

Julia Dörner, Verena Martinez Rodriguez, Ricarda Ziegler, Theresa Röhrig, Rebecca S. Cochran, Ronni M. Götz, Mark D. Levin, Marjut Pihlajoki, Markku Heikinheimo, David B. Wilson

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4 Scopus citations

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.

Original languageEnglish
Pages (from-to)164-175
Number of pages12
JournalMolecular and Cellular Endocrinology
Volume441
DOIs
StatePublished - Feb 5 2017

Keywords

  • Adrenal cortex
  • Gonadectomy
  • Gonadotropin
  • Lineage tracing
  • Orchiectomy
  • Ovariectomy

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    Dörner, J., Martinez Rodriguez, V., Ziegler, R., Röhrig, T., Cochran, R. S., Götz, R. M., Levin, M. D., Pihlajoki, M., Heikinheimo, M., & Wilson, D. B. (2017). GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue. Molecular and Cellular Endocrinology, 441, 164-175. https://doi.org/10.1016/j.mce.2016.08.043