Six2 is involved in GATA1-mediated cell apoptosis in mouse embryonic kidney-derived cell lines.

Six2 (Sine oculis homeobox 2), a homeodomain transcription factor, plays a crucial role in the regulation of mammalian nephrogenesis. It is also implicated in numerous biological functions, such as cell proliferation, apoptosis, and migration. However, the underlying regulatory mechanisms of Six2 remain largely unknown. In this study, we predicted that CRX, GATA1, HOXD8, and POU2F2 might target, binding to the promoter region of Six2 (~2000 bp) by bioinformatics analysis. Among the four genes, the predicted binding sequence of GATA1 is most highly conserved across species. Luciferase assays demonstrated that knockdown of GATA1 decreased the activity of Six2 promoter and qPCR result of Six2 expression was in consistent with this in 293T cells. Mutation of GATA1 binding sites of mSix2 promoter led to obvious decrease of the mSix2 promoter activity. Furthermore, knockdown of GATA1 decreased Six2 expression in mk3 cells and increased cell apoptosis of mk3 and mk4 compared with corresponding control cells, but this up-regulation can be rescued by Six2 overexpression. Our findings indicated that GATA1 may be a potential regulator of Six2-maintained population of nephron progenitor cells.