Description:
<jats:p>A functional vertebrate kidney relies on structural units called nephrons, which are epithelial tubules that contain a sequence of segments each expressing a distinct repertoire of solute transporters. To date, the transcriptional codes driving regional specification, solute transporter program activation, and terminal differentiation of segment populations remains poorly understood. We demonstrate for the first time that the KCTD15 paralogs, <jats:italic>kctd15a</jats:italic> and <jats:italic>kctd15b</jats:italic>, 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 co‐localized with <jats:italic>tfap2a</jats:italic> in distal tubule precursors. <jats:italic>kctd15</jats:italic> loss primed nephron cells to adopt distal fates by driving expansions in <jats:italic>slc12a1</jats:italic>, <jats:italic>kcnj1a.1</jats:italic>, and <jats:italic>stc1</jats:italic> marker expression. These phenotypes were resultant of Tfap2a hyperactivity, where <jats:italic>kctd15a/b</jats:italic>‐deficient embryos exhibited increased abundance of this transcription factor. Interestingly, <jats:italic>tfap2a</jats:italic> can reciprocally promote <jats:italic>kctd15</jats:italic> transcription, unveiling a circuit of autoregulation operating in nephron tubule progenitors. Concomitant <jats:italic>kctd15b</jats:italic> knockdown with <jats:italic>tfap2a</jats:italic> overexpression produced genetic synergy and uncontrolled DE/TAL differentiation. Our data indicates nephron segmentation is determined by a transcription factor‐repressor feedback module that employs tight regulation of Tfap2a‐Kctd15 kinetics during kidney development.</jats:p>