SYM-15-05

Heterozygosity for SIX2 increases nephron progenitor expansion and final nephron number

AN Combes1,2, S Wilson2, B Phipson2, B Binnie3, A Ju4, C Cebrian5, S Walton6, K Moritz6, O Oshlack2 and MH Little1,7

  1. Department of Anatomy & Neuroscience, University of Melbourne
  2. Murdoch Childrens Research Institute
  3. Institute for Molecular Bioscience, The University of Queensland
  4. Translational Research Institute, The University of Queensland
  5. Department of Internal Medicine, University of Michigan
  6. School of Biomedical Sciences, The University of Queensland
  7. Department of Paediatrics, The University of Melbourne

Homozygous loss of transcriptional regulator Six2 results in premature differentiation of the nephron progenitor population and an early halt to kidney development in mice. SIX2 levels are high in the slow-cycling undifferentiated progenitor pool and lower in faster cycling progenitors that have been induced to form a new nephron. Current regulatory models include a change in SIX2 protein levels to drive these alternative fates. This study aimed to determine whether kidney morphogenesis was altered by the loss of a single allele of Six2. Lowering Six2 levels was anticipated to result in a premature loss of progenitors, decreased kidney growth, and lower nephron number. However, quantitative multiscale imaging and transcriptional profiling revealed the opposite. Six2 Het mice had an 18% increase in the amount of branching morphogenesis during development and a proportional increase in final nephron number in adulthood. Proliferation was increased in the progenitor pool, possibly due to dephosphorylation of MYC by elevated levels of EYA1 phosphatase. Direct and dose-sensitive SIX2 targets were identified by further analysing transcriptional changes in Six2 KO and Het kidneys, with these target genes showing high overlap with published SIX2 ChIP data. Recent studies have shown that reducing nephron progenitor number during development causes a reduction in final nephron number. This data demonstrates the converse- that nephron number can be augmented by expansion of the progenitor pool. It also suggests a dose-sensitive separation between the role of SIX2 in regulating proliferation and the maintenance of progenitor identity.