Eya1 Interacts with Six2 and Myc to Regulate Expansion of the Nephron Progenitor Pool during Nephrogenesis

Self-renewal and proliferation of nephron progenitor cells and the decision to initiate nephrogenesis are crucial events directing kidney development. Despite recent advancements in defining lineage and regulators for the progenitors, fundamental questions about mechanisms driving expansion of the progenitors remain unanswered. Here we show that Eya1 interacts with Six2 and Myc to control self-renewing cell activity. Cell fate tracing reveals a developmental restriction of the Eya1+ population within the intermediate mesoderm to nephron-forming cell fates and a common origin shared between caudal mesonephric and metanephric nephrons. Conditional inactivation of Eya1 leads to loss of Six2 expression and premature epithelialization of the progenitors. Six2 mediates translocation of Eya1 to the nucleus, where Eya1 uses its threonine phosphatase activity to control Myc phosphorylation/dephosphorylation and function in the progenitor cells. Our results reveal a functional link between Eya1, Six2, and Myc in driving the expansion and maintenance of the multipotent progenitors during nephrogenesis. •Caudal mesonephric and metanephric nephrons share a common origin of Eya1+ cells•Six2 mediates nuclear translocation of Eya1 in nephron progenitors•Nuclear Eya1 activity regulates the postphosphorylation modification of Myc•Eya1 dephosphorylates Myc at T58 to prevent its degradation Eya nuclear phosphatases collaborate with Six family transcription factors to control gene expression. Xu et al. find that Six2 enhances nuclear localization of Eya1, which, in turn, dephosphorylates Myc transcription factors. The resulting stabilization of Myc contributes to Eya1/Six2 effects on nephron progenitor proliferation.