Six1 and Six2 of the sine oculis homeobox subfamily are not functionally interchangeable in mouse nephron formation

ABSTRACT: The vertebrate Six1 and Six2 arose by gene duplication from the Drosophila so (sine oculis) and have since diverged in their developmental expression patterns. Both genes are expressed in nephron progenitors of human fetal kidneys, and mutations in SIX1 or SIX2 cause branchio-oto-renal or renal hypodysplasia respectively. Since ~80% of SIX1 target sites are shared by SIX2, it is speculated that SIX1 and SIX2 may be functionally interchangeable by targeting common downstream genes. In contrast, in mouse kidneys, the expression of Six1 and Six2 only transiently overlaps in the metanephric mesenchyme before the onset of ureteric branching, and only Six2 expression is maintained in the nephron progenitors throughout development. This non-overlapping expression between Six1 and Six2 in mouse nephron progenitors promoted us to examine if Six1 can replace Six2. Surprisingly, forced expression of Six1 failed to rescue Six2-deficient kidney hypoplasia. We found that Six1 mediated Eya1 nuclear translocation and inhibited premature epithelialization of the progenitors but failed to rescue the proliferation defects and cell death caused by Six2-knockout. Genome-wide binding analyses showed that Six1 only bound to a small subset of Six2 target sites, but many Six2-bound loci that are crucial to the renewal and differentiation of nephron progenitors lacked Six1 occupancy. Thus, these data indicate that Six1 cannot substitute Six2 to drive nephrogenesis in mouse kidneys, demonstrating that these two transcription factors have not maintained equivalent biochemical properties since their divergence early in vertebrate evolution.

ORGANISM(S): Mus musculus

PROVIDER: GSE189131 | GEO | 2022/01/27

REPOSITORIES: GEO