COUP-TFII is essential for metanephric mesenchyme formation and kidney precursor cell survival

Abstract

SUMMARYDevelopment of the metanephric kidney in mammals requires complex reciprocal tissue interactions between the ureteric epithelium and the mesenchyme. It is believed that Gdnf, produced in the metanephric mesenchyme, activates Ret signaling in the Wolffian duct to initiate the formation of the metanephros. However, the molecular mechanism for induction of Gdnf in the metanephric mesenchyme is not completely defined. Previous studies demonstrated that during the early stages of kidney development, loss of Osr1, Eya1, Pax2 or Wt1 gene function in the metanephric mesenchyme compromises the formation of the kidney. Moreover, it has been shown that the Hox11-Eya1-Pax2 complex activates the expression of Six2 and Gdnf in the metanephric mesenchyme to drive nephrogenesis. Here, we demonstrate that the orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor II (COUP-TFII, also known as Nr2f2) is required for the specification of the metanephric mesenchyme. Deletion of COUP-TFII at E7.5 results in improper differentiation of the metanephric mesenchyme and absence of essential developmental regulators, such as Eya1, Six2, Pax2 and Gdnf. Importantly, we show that COUP-TFII directly regulates the expression of both Eya1 and Wt1 in the metanephric mesenchyme. Our findings reveal, for the first time, that COUP-TFII plays a central role in the specification of metanephric fate and in the maintenance of metanephric mesenchyme proliferation and survival by acting as a crucial regulator of Eya1 and Wt1 expression.

COUP-TFs and eye development

“…Furthermore, GST pull-down analysis reveals that COUP-TFI and Sp1 physically interact in vitro [100]. Accumulating evidence supports that COUP-TFs activate gene expression through tethering to the Sp1 transcription factor, which binds at the Sp1 site of the target genes, such as Otx2 in the eye [16, 19, 20, 24, 27, 36, 71, 73, 100–102] (Fig 1B; Table 2). Consistent with this conclusion, chromatin immunoprecipitation assay (ChIP) indicates that COUP-TF is recruited to the Sp1 site and knockdown of Sp1 or mutation of the Sp1 binding site eliminates the recruitment of COUP-TF to the Sp1 site [16, 71, 73, 100]…”

Genome-wide identification, evolution and expression analysis of nuclear receptor superfamily in Nile tilapia, Oreochromis niloticus

“…For example, COUP-TFβ is known to be required for heart development, temporal specification of neural stem cells, kidney precursor cell survival and male fertility in mammals Naka et al, 2008;Qin et al, 2008;Yu et al, 2012). In adult tilapia, COUP-TFβ-A was preferentially expressed in the brain, heart, kidney and testis, while its paralog, COUP-TFβ-B, was not or very weakly expressed in all of the 8 tissues examined.…”

Assessment of promoter methylation and expression of SIX2 as a diagnostic and prognostic biomarker in Wilms’ tumor

“…Survival analysis showed that the methylation level of the SIX2 gene is significantly associated with clinical outcome for WT, suggesting that measurement of methylated SIX2 promoter DNA in tissue may contribute to improved estimation of the postoperative survival chances of these patients. Critical upstream activators of SIX2, such as EYA1, HOXA11, HOXD11, Wnt9b, and PAX2, are known to play a regulatory role during the expression process [36][37][38]. However, the mechanisms and specific roles of these genes in the initiation and development of WT are currently unknown.…”