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GATA4 is a critical regulator of gonadectomy-induced adrenocortical tumorigenesis in mice
Justyna Krachulec1, Melanie Vetter, Anja Schrade
1Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
Abstract:
In response to gonadectomy certain inbred mouse strains develop sex steroidogenic adrenocortical neoplasms. One of the hallmarks of neoplastic transformation is expression of GATA4, a transcription factor normally present in gonadal but not adrenal steroidogenic cells of the adult mouse. To show that GATA4 directly modulates adrenocortical tumorigenesis and is not merely a marker of gonadal-like differentiation in the neoplasms, we studied mice with germline or conditional loss-of-function mutations in the Gata4 gene. Germline Gata4 haploinsufficiency was associated with attenuated tumor growth and reduced expression of sex steroidogenic genes in the adrenal glands of ovariectomized B6D2F1 and B6AF1 mice. At 12 months after ovariectomy, wild-type B6D2F1 mice had biochemical and histological evidence of adrenocortical estrogen production, whereas Gata4(+/-) B6D2F1 mice did not. Germline Gata4 haploinsufficiency exacerbated the secondary phenotype of postovariectomy obesity in B6D2F1 mice, presumably by limiting ectopic estrogen production in the adrenal glands. Amhr2-cre-mediated deletion of floxed Gata4 (Gata4(F)) in nascent adrenocortical neoplasms of ovariectomized B6.129 mice reduced tumor growth and the expression of gonadal-like markers in a Gata4(F) dose-dependent manner. We conclude that GATA4 is a key modifier of gonadectomy-induced adrenocortical neoplasia, postovariectomy obesity, and sex steroidogenic cell differentiation.
Insights
The transcription factor GATA4 drives the development of sex steroidogenic adrenocortical neoplasms and associated obesity in mice after gonadectomy. Loss of GATA4 function reduces tumor growth and estrogen production, highlighting its critical role.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Gonadectomy in certain mouse strains induces sex steroidogenic adrenocortical neoplasms.
- GATA4, a transcription factor, is expressed in these neoplasms but not in normal adrenal cells.
Purpose of the Study:
- To determine if GATA4 directly influences adrenocortical tumorigenesis and steroidogenesis.
- To investigate GATA4's role in post-gonadectomy obesity.
Main Methods:
- Studied mice with germline or conditional loss-of-function mutations in the Gata4 gene.
- Analyzed tumor growth, gene expression, and hormone production in ovariectomized mice.
- Utilized Amhr2-cre-mediated deletion of Gata4(F) in nascent neoplasms.
Main Results:
- Germline Gata4 haploinsufficiency attenuated tumor growth and sex steroidogenic gene expression in ovariectomized mice.
- Gata4 haploinsufficiency prevented adrenocortical estrogen production and exacerbated post-ovariectomy obesity.
- Conditional Gata4 deletion reduced tumor growth and gonadal marker expression in a dose-dependent manner.
Conclusions:
- GATA4 is a key modifier of gonadectomy-induced adrenocortical neoplasia.
- GATA4 plays a crucial role in sex steroidogenic cell differentiation in the adrenal glands.
- GATA4 influences post-gonadectomy obesity, likely through its effects on ectopic estrogen production.
