Differential gene dosage effects of Ad4BP/SF-1 on target tissue development

Fatchiyah,; Zubair, Mohamad; Shima, Yuichi; Oka, Sanae; Ishihara, Satoru; Fukui-Katoh, Yuko; Morohashi, Ken Ichirou

doi:10.1016/j.bbrc.2006.01.058

Cited by 37 publications

(17 citation statements)

References 30 publications

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“…This indicates that adrenal development is more sensitive to Sf-1 dosage than gonadal development in mouse. Consistent with this, transgenic overexpression of Sf-1 rescued the gonad but not the adrenal defect in Sf-1 -/-mice, although the transgenic constructs were expressed in both tissues in wild-type animals (Fatchiyah et al, 2006). Therefore, our data strongly suggest that Sf-1 dosage has to reach a critical threshold in the AGP to trigger adrenal development and that Cited2 is required to raise Sf-1 expression above this threshold.…”

Section: Discussionsupporting

confidence: 83%

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

2007

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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.

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Section: Discussionsupporting

confidence: 83%

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

2007

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“…However, a more predominant dosage-sensitive effect of SF-1 on adrenal rather than gonadal formation has been suggested from a finding of the predominant reduction of adrenal size in heterozygous SF-1 KO mice [52]. A similar finding has recently been reported in an experiment that Ad4BP/SF-1 transgenic mice harboring varied expression levels of SF-1 among tissues were applied to rescue homozygous Ad4BP/SF-1 KO mice; the transgenic mice failed to rescue the adrenal gland, but successfully rescued the gonad and spleen [53]. Therefore, one approach to direct the steroidogenic cell lineage might be to control Ad4BP/SF-1 expression levels or Ad4BP/SF-1 transcriptional activity in BMC cells.…”

Section: Discussionsupporting

confidence: 67%

Differentiation and Regeneration of Adrenal Tissues: An Initial Step toward Regeneration Therapy for Steroid Insufficiency

et al. 2006

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Abstract. In animal experiments, adrenal cortical tissue has been successfully regenerated through xenotransplantation of cloned adrenocortical cells, suggesting that the intraadrenal stem cells required for such tissue formation may be present in the adrenal cortex. Stable expression of Ad4BP/SF-1, a key factor for adrenal and gonadal development and steroidogenesis, has been shown to direct embryonic stem cells toward the steroidogenic lineage. However, this steroidogenic capacity was very limited since progesterone was only produced in the presence of an exogenous substrate. Bone marrow mesenchymal cells are thought to contain pluripotent progenitor cells, which differentiate into multiple lineages. We have demonstrated that adenovirus-mediated forced expression of SF-1 in long-term cultured bone marrow cells can produce steroidogenic cells with the capacity for de novo synthesis of various steroid hormones in response to ACTH. This discovery may represent the first step in autologous cell transplantation therapy for patients with steroid hormone deficiency.

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“…This suggested that adrenal development in mouse was more sensitive to decreased Sf-1 dosage than gonadal development. Consistent with this, forced transgenic expression of Sf-1 in Sf-1 mutant mice rescued gonad development but not adrenal development, even though the transgene was expressed in both tissues in control animals [47]. In our experiments, Sf-1 expression levels in the E10.5 AGP correlated with the severity of the adrenal phenotype.…”

Section: Cited2 Wt1 and Sf-1 Dosagesupporting

confidence: 87%

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

Val

Swain

2010

Molecular and Cellular Endocrinology

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Differential gene dosage effects of Ad4BP/SF-1 on target tissue development

Cited by 37 publications

References 30 publications

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

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

Differentiation and Regeneration of Adrenal Tissues: An Initial Step toward Regeneration Therapy for Steroid Insufficiency

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

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