Kctd15 regulates nephron segment development by repressing Tfap2a activity

Abstract

A functional vertebrate kidney relies on structural units called nephrons, which are epithelial tubules with a sequence of segments each expressing a distinct repertoire of solute transporters. The transcriptional codes driving regional specification, solute transporter program activation and terminal differentiation of segment populations remain poorly understood. Here, we demonstrate that the KCTD15 paralogs kctd15a and kctd15b function in concert to restrict distal early (DE)/thick ascending limb (TAL) segment lineage assignment in the developing zebrafish pronephros by repressing Tfap2a activity. During renal ontogeny, expression of these factors colocalized with tfap2a in distal tubule precursors. kctd15a/b loss primed nephron cells to adopt distal fates by driving slc12a1, kcnj1a.1 and stc1 expression. These phenotypes were the result of Tfap2a hyperactivity, where kctd15a/bdeficient embryos exhibited increased abundance of this transcription factor. Interestingly, tfap2a reciprocally promoted kctd15a and kctd15b transcription, unveiling a circuit of autoregulation operating in nephron progenitors. Concomitant kctd15b knockdown with tfap2a overexpression further expanded the DE population. Our study reveals that a transcription factor-repressor feedback module employs tight regulation of Tfap2a and Kctd15 kinetics to control nephron segment fate choice and differentiation during kidney development.