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Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret

ABSTRACT: Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Complementary approaches, including DNA methylation mapping and microarray expression profiling, were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated by quantitative RT-PCR, laser capture microdissection, in situ hybridization, and immunohistochemistry. Two genes with hypomethylated promoters, Igfbp6 and Foxs1, were upregulated in post-GDX adrenocortical neoplasms. The neoplastic cells also exhibited hypomethylation of the fetal adrenal enhancer of Sf1, an epigenetic signature that typifies descendants of fetal adrenal rather than gonadal cells. Expression profiling demonstrated upregulation of gonadal-like genes, including Spinlw1, Insl3, and Foxl2, in GDX-induced adrenocortical tumors of the mouse. One of these markers, FOXL2, was detected in adrenocortical tumor specimens from gonadectomized ferrets. These new markers may prove useful for studies of steroidogenic cell development and for diagnostic testing.

ORGANISM(S): Mus musculus

PROVIDER: GSE54393 | GEO | 2014/07/31

SECONDARY ACCESSION(S): PRJNA236384

REPOSITORIES: GEO

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Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret

Project description:Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Complementary approaches, including DNA methylation mapping and microarray expression profiling, were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated by quantitative RT-PCR, laser capture microdissection, in situ hybridization, and immunohistochemistry. Two genes with hypomethylated promoters, Igfbp6 and Foxs1, were upregulated in post-GDX adrenocortical neoplasms. The neoplastic cells also exhibited hypomethylation of the fetal adrenal enhancer of Sf1, an epigenetic signature that typifies descendants of fetal adrenal rather than gonadal cells. Expression profiling demonstrated upregulation of gonadal-like genes, including Spinlw1, Insl3, and Foxl2, in GDX-induced adrenocortical tumors of the mouse. One of these markers, FOXL2, was detected in adrenocortical tumor specimens from gonadectomized ferrets. These new markers may prove useful for studies of steroidogenic cell development and for diagnostic testing. Total RNA extracted from whole adrenal glands of gonadectomized and non-gonadectomized mice.

2014-07-31 | E-GEOD-54393 | biostudies-arrayexpress

The developmental origin and the specification of the adrenal cortex in humans and cynomolgus monkeys

Project description:Development of the adrenal cortex, a vital endocrine organ, originates in the adrenogonadal primordium, a common progenitor for both the adrenocortical and gonadal lineages in rodents. In contrast, we find that in humans and cynomolgus monkeys, the adrenocortical lineage originates in a temporally and spatially distinct fashion from the gonadal lineage, arising earlier and more anteriorly within the coelomic epithelium. The adrenal primordium arises from adrenogenic coelomic epithelium via an epithelial-to-mesenchymal-like transition, which then progresses into the steroidogenic fetal zone via both direct and indirect routes. Notably, we find that adrenocortical and gonadal lineages exhibit distinct HOX codes, suggesting distinct anterior-posterior regionalization. Together, our assessment of the early divergence of these lineages provides a molecular framework for understanding human adrenal and gonadal disorders.

2022-04-20 | GSE193672 | GEO

Genome wide analysis of Adrenal Gland tissue from Gata6 conditional knockout versus Control Adrenal tissue

Project description:Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex with thickened capsule. Cytomegalic changes were evident in the adrenal glands of fetal and adult cKO mice, and chromaffin cells were ectopically located at the periphery of the glands. The secretion of corticosterone in response to exogenous ACTH was blunted in cKO mice. Cells expressing gonadal-like markers, including Gata4, Amhr2, and Tcf21, accumulated in the adrenal capsule and subcapsule of cKO mice, suggesting aberrant adrenocortical progenitor/stem cell differentiation. Gonadectomy triggered the overexpression of sex steroidogenic differentiation markers, such as Lhcgr and Cyp17, in the adrenal glands of male and female cKO mice. Nulliparous female and orchiectomized male cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of nulliparous female Gata6 cKO mice. Our findings offer genetic proof of the longstanding hypothesis that GATA6 regulates the differentiation of steroidogenic progenitors into corticoid-producing cells. 3 replicates from both conditional knockout of Gata6 in the adrenal gland and control adrenal glands from non-knockout mice were compared

2013-06-06 | E-GEOD-40398 | biostudies-arrayexpress

Genome wide analysis of Adrenal Gland tissue from Gata6 conditional knockout versus Control Adrenal tissue

2013-06-06 | GSE40398 | GEO

Expression data from mouse adrenal glands extracted from wild-type (WT) and Cyp11b2tm1.1(cre)Brlt;Prkar1afl/fl(KO) adrenals

Project description:We demonstrate that PKA signalling drives zonal conversion within adult adrenocortical lineage in a sexually dimorphic manner. Our data establish that Prkar1a genetic ablation (leading to constitutive PKA activation) in the adult adrenocortical lineage leads to endocrine hyperactivity and accelerates adrenal cortex renewal. This results in increased zona fasciculata differentiation and final conversion into reticularis-like zone. This phenomenon relies partly on sex-dependent mechanisms of cortical renewal, on which the male androgenic milieu exerts a repressive action through induction of WNT signalling, which in turn antagonizes PKA signalling and cortical cell turnover. We used microarrays to analyse gene expression in response to Prkar1a gene ablation in the adult adrenocortical cell lineage in both female and male mice and explored the effects of orchidectomy (GDX).

2017-09-16 | GSE103899 | GEO

Identification of genes regulated in adrenal glands of Ftz-F1 transgenic mice

Project description:SF-1, a transcription factor belonging to the nuclear receptor superfamily, has a pivotal role for adrenogonadal development in humans and mice. A constant feature of childhood adrenocortical tumors (ACT) is SF-1 amplification and overexpression. Using an inducible cellular system, here we show that SF-1 overexpression increases human adrenocortical cell proliferation through opposing effects on cell cycle and apoptosis. SF-1 overexpression also selectively modulates steroidogenesis, reducing cortisol and aldosterone secretion. We identified a novel pro-apoptotic factor for adrenocortical cells, NOV/CCN3, whose levels are significantly reduced by SF-1 overexpression in human adrenocortical cells and are also reduced in primary adrenal tumors. Moreover, Sf-1 overexpression triggers adrenocortical hyperplasia and tumor formation in mice. These tumors express gonadal markers and activated Stat3. Our studies reveal the critical role of SF-1 gene dosage for adrenocortical tumorigenesis and constitute a rationale for the development of drugs targeting SF-1 transcriptional activity for ACT therapy. Keywords: comparative gene expression

2007-01-01 | GSE5912 | GEO

Identification of genes regulated by overexpressed SF-1 in human adrenocortical cells

2007-01-01 | GSE5911 | GEO

Genome-wide analysis of fetal adrenocortical cells gene expression after 48 h ACTH treatment

Project description:Analysis of ACTH-regulation on adrenocortical cells at gene expression level. The hypothesis tested in the present study was that ACTH increases chronic cell growth and steroidogenesis in adrenal glands by changing the gene expression profile. Results provide important information on the changes of gene expression of adrenocortical cells after chronic ACTH treatment. Total RNA obtained from primary cultured fetal adrenal cells subjected to 48 hours in vitro treatment of ACTH compared to untreated control cell.

2010-07-08 | E-GEOD-20675 | biostudies-arrayexpress

Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells [scRNA-seq]

Project description:The adrenal cortex produces vital steroid hormones that maintain homeostasis. While steroid hormones produced from the fetal zone adrenal cortex are essential for both fetal development and maintenance of pregnancy, the molecular mechanisms leading to human adrenal cortex development and steroid synthesis remain poorly understood due to the paucity of model systems. Through progressive generation of fetal zone adrenal cortex-like cells (FZLCs) from human induced pluripotent stem cells through posterior intermediate mesoderm-like, adrenogenic coelomic epithelium and adrenal primordium-like states, we provide the first in vitro reconstitution of human adrenocortical fetal specification. Generation of FZLCs faithfully recapitulates human embryonic adrenal cortex specification as evidenced by histomorphological and ultrastructural analysis, transcriptional profiles and delta-5 steroid biosynthesis and occurs in an adrenocorticotropic hormone (ACTH)-independent manner, consistent with clinical observations. Furthermore, we demonstrate that FZLC generation is promoted by SHH and inhibited by NOTCH, ACTIVIN and WNT signaling and that steroid synthesis is amplified by ACTH/PKA signaling and blocked by pharmacologic inhibitors of delta 5 steroid synthesis enzymes. Finally, NR5A1 appear to self-stabilize its promoter activity and promote FZLC survival and steroidogenesis. Together, these findings provide a framework for understanding and reconstituting human adrenocortical development in vitro and pave the way for future cell-based therapies of adrenal insufficiency.

2022-10-16 | GSE201794 | GEO

Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells [scATAC-seq]

2022-10-16 | GSE201793 | GEO

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