<i>ppargc1a</i> controls nephron segmentation during zebrafish embryonic kidney ontogeny.

Abstract

Nephron segmentation involves a concert of genetic and molecular signals that are not fully understood. Through a chemical screen, we discovered that alteration of peroxisome proliferator-activated receptor (PPAR) signaling disrupts nephron segmentation in the zebrafish embryonic kidney (Poureetezadi et al., 2016). Here, we show that the PPAR co-activator <i>ppargc1a</i> directs renal progenitor fate. <i>ppargc1a</i> mutants form a small distal late (DL) segment and an expanded proximal straight tubule (PST) segment. <i>ppargc1a</i> promotes DL fate by regulating the transcription factor <i>tbx2b,</i> and restricts expression of the transcription factor <i>sim1a</i> to inhibit PST fate. Interestingly, <i>sim1a</i> restricts <i>ppargc1a</i> expression to promote the PST, and PST development is fully restored in <i>ppargc1a/sim1a</i>-deficient embryos, suggesting Ppargc1a and Sim1a counterbalance each other in an antagonistic fashion to delineate the PST segment boundary during nephrogenesis. Taken together, our data reveal new roles for Ppargc1a during development, which have implications for understanding renal birth defects.