Role for compartmentalization in nephron progenitor differentiation

Embryonic nephron progenitor cells are segregated in molecularly distinct compartments of unknown function. Our study reveals an integral role for bone morphogenetic protein-SMAD in promoting transition of progenitors from the primitive Cbp/p300-interacting transactivator 1 expressing (CITED1+) compartment to the uniquely sine oculis-related homeobox 2 expressing (SIX2-only) compartment where they become inducible by wingless-type mouse mammary tumor virus integration site family member (WNT)/beta-catenin signaling. Significantly, CITED1(+) cells are refractory to WNT/beta-catenin induction. We propose a model in which the primitive CITED1(+) compartment is refractory to induction by WNT9b/beta-catenin, ensuring maintenance of undifferentiated progenitor cells for future nephrogenesis. Bone morphogenetic protein 7-SMAD is then required for transition to a distinct compartment in which cells become inducible by WNT9b/beta-catenin, allowing them to progress toward epithelialization.