Transgenic Expression ofAd4BP/SF-1in Fetal Adrenal Progenitor Cells Leads to Ectopic Adrenal Formation

Abstract

Deficiency of adrenal 4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1; NR5A1) impairs adrenal development in a dose-dependent manner, whereas overexpression of Ad4BP/SF-1 is associated with adrenocortical tumorigenesis. Despite its essential roles in adrenal development, the mechanism(s) by which Ad4BP/SF-1 regulates this process remain incompletely understood. We previously identified a fetal adrenal enhancer (FAdE) that stimulates Ad4BP/SF-1 expression in the fetal adrenal gland by a two-step mechanism in which homeobox proteins initiate Ad4BP/SF-1 expression, which then maintains FAdE activity in an autoregulatory loop. In the present study, we examined the effect of transgenic expression of Ad4BP/SF-1 controlled by FAdE on adrenal development. When Ad4BP/SF-1 was overexpressed using a FAdE-Ad4BP/SF-1 transgene, FAdE activity expanded outside of its normal field, resulting in increased adrenal size and the formation of ectopic adrenal tissue in the thorax. The increased size of the adrenal gland did not result from a corresponding increase in cell proliferation, suggesting rather that the increased levels of Ad4BP/SF-1 may divert uncommitted precursors to the steroidogenic lineage. The effects of FAdE-controlled Ad4BP/SF-1 overexpression in mice provide a novel model of ectopic adrenal formation that further supports the critical role of Ad4BP/SF-1 in the determination of steroidogenic cell fate in vivo.

Prevalence of Testicular Adrenal Rest Tissue in Neonates

“…Disruption of the Ftz-F1 gene in mice, which encodes for Ad4BP/SF-1, results in both absence of adrenal glands and gonads [18]. In contrast, recent transgenic mice experiments demonstrated that Ad4BP/SF-1 overexpression results in gonadal tissue remaining adjacent to the kidneys [19]. …”

Development of Adrenal Cortex Zonation

“…Studies by Zubair, et al provided significant insights into the relationship between the FZ and the DZ/adult cortex 26, 27, 59, 60 . Using the FAdE-Cre mouse model, these investigators observed proliferating cells in a scattered pattern throughout the adrenal gland until E13.5 13, 60 .…”

Adrenocortical development and cancer: focus on SF-1

“…Modulation of SF-1 dosage is also relevant for the mechanism of adrenal development impairment induced by the lack of CITED2, a transcriptional cofactor supposedly interacting with WT1 (Val et al 2007). On the other hand, transgenic overexpression of SF-1 in mice under the control of its own FAdE led to increased adrenal size and to the formation of ectopic adrenal tissue in the thorax (Zubair et al 2009). All together, these data evidence the importance of SF-1 dosage for both adrenal and gonadal development.…”