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.

Probing GATA factor function in mouse Leydig cells via testicular injection of adenoviral vectors

“…RNA was isolated from whole testes (Kyrönlahti et al 2011) and subjected to RT-qPCR analysis as described (Dörner et al 2017), using the primers listed in Table 2. Expression was normalized to the housekeeping genes Gapdh and Actb .…”

Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex

“…4 B, d vs. c). Although homeostatic renewal of the cortex occurs mainly through recruitment of SF1-positive, SHH-positive cells located in the vicinity of zG (6), a number of SF1-negative cells expressing WT1, GLI1, or GATA4 can be recruited to meet supraphysiological demand or in models of adrenal insufficiency (6,(18)(19)(20). Interestingly, analysis of microarray data showed up-regulation of Gata4, Wt1, and Gli1, suggesting that supraphysiological progenitors may be accumulating in Ezh2 KO adrenals (Fig.…”

“…We then sought to determine the origin of this phenotype. GATA4 and WT1 cells have been shown to accumulate in the adrenal cortex of mice following castration (18,19). Although Sf1:Cre is also active in the gonad, Sf1:Cre,Ezh2 Fl/Fl mice of both sexes were fertile (SI Appendix, Fig.…”

Luteinizing Hormone and GATA4 Action in the Adrenocortical Tumorigenesis of Gonadectomized Female Mice

“…AGP cells differentiate into gonadal and adrenal primordium and later into independent organs [1] although, recently AGP-like cells were found in the capsule of the mouse adrenal cortex [2]. Therefore disrupted endocrine homeostasis, e.g.…”

“…Therefore disrupted endocrine homeostasis, e.g. due to gonadectomy (GDX) may promote the differentiation of AGP progenitors into neoplastic cells bearing gonadal-like phenotype [2]. Most of the wild-type (WT) mouse strains develop sub-capsular, non-steroidogenic, spindle-shaped A cells when aging [3, 4].…”