Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage

Abstract

It has been proposed that the mammalian adrenal cortex and gonad are derived from the same primordium present during early urogenital development. Molecular pathways involved in the differentiation of the adrenal cortex from the adrenogonadal primordium (AGP) have yet to be determined. Here we show in mice that the transcription co-factor Cited2 is required for the specification of the adrenal cortex from the AGP. We present genetic and molecular evidence demonstrating that Cited2 interacts with the transcription factor Wt1 to stimulate expression of the nuclear hormone receptor Sf-1 (Nr5a1) in the AGP prior to the separation between gonad and adrenal cortex. We show a direct correlation between the expression levels of Sf-1 in the AGP and the defects in adrenal development found in mice with different Cited2 and Wt1 mutant backgrounds. Analysis of embryos heterozygous for mutations in both Sf-1 and Cited2 confirmed that these genes act in the same pathway during adrenal development. Our studies reveal a regulatory mechanism in which Cited2 acts as a Wt1 co-factor to increase, at a critical time in embryogenesis, the levels of the essential transcription factor Sf-1 in the AGP above the threshold required to determine adrenal development. These results highlight the importance of transcription factor dosage in organogenesis and the role of transcription co-factors such as Cited2 in determining the levels of these factors.

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

“…1a,b). Consistent with previous reports [18][19][20][21] , the treated cells were decreased in number, probably due to decreased proliferation (Fig. 1c,d).…”

Gene dosage effects and transcriptional regulation of early mammalian adrenal cortex development

“…We demonstrated that this essential role of Cited2 was dependent on its physical and functional interaction with Wt1 in the AGP, prior to adrenal formation. This interaction resulted in increased Sf-1 promoter activity and Sf-1 expression [20] (Fig2). Other studies have shown that modulations of Sf-1 dosage can affect gonadal and adrenal development to different degrees.…”

“…In mouse, Sf-1 was detected as early as E9.0. The process of AGP development was similar and the adrenal anlage separated from the bipotential precursor at E10.5 (10-11 tail somites) [19,20] …”

“…Using transgenic mice, they showed that Wt1 was directly activating transcription of Sf-1 through four Wt1 responsive elements found in a 674 bp promoter fragment that recapitulated Sf-1 expression in the urogenital ridges [32]. We have recently demonstrated that Wt1, in association with Cited2, plays an essential role in modulating Sf-1 dosage and triggering adrenal cortex differentiation ( [20], see chapter II).…”

“…With 36% of wild-type dosage, as seen in Cited2-/-embryos, adrenal development was not initiated, whereas with 45% of wild-type levels, as seen in Cited2+/-Wt1+/-embryos, adrenal development was initiated but adrenal growth was markedly impaired. Therefore we proposed that Sf-1 dosage had to reach a critical threshold, at a particular stage, to trigger adrenal development from the AGP and that Cited2, together with Wt1, were required to increase Sf-1 expression above that threshold (Fig2) [20]. It is intriguing that Wt1, which is not found in the overtly differentiated adrenal [20,48], plays an essential role for its determination from the AGP.…”