PLX189324

GSE103219: Haploinsufficiency for SIX2 increases nephron progenitor proliferation leading to elevated branching and nephron number

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

The regulation of final nephron number in the kidney is poorly understood. However, cessation of nephron formation occurs when the self-renewing nephron progenitor population commits to differentiation. Transcription factors within this progenitor population, such as SIX2, are assumed to control expression of genes promoting self-renewal such that homozygous Six2 deletion results in premature commitment and an early halt to kidney development. In contrast, Six2 heterozygotes were assumed to be unaffected. Using quantitative morphometry, we demonstrate here a paradoxical 18% increase in ureteric branching and final nephron number in Six2 heterozygotes, despite evidence for reduced levels of SIX2 protein and transcript. This is accompanied by a clear shift in nephron progenitor identity with a distinct subset of progenitor genes, including Cited1 and Meox1, downregulated, while others were unaffected. The net result was an increase in nephron progenitor proliferation, as assessed by elevated EDU labelling, an increase in MYC protein and transcriptional upregulation of MYC target genes. Reducing proliferation by introducing Six2 heterozygosity onto the Fgf20-/- background resulted in premature differentiation of the progenitor population. Overall, this data demonstrates a unique dose response of the nephron progenitors to the level of SIX2 protein in which the role of SIX2 in progenitor proliferation versus self-renewal is separable. SOURCE: Belinda PhipsonBioinformatics Murdoch Childrens Research Institute