Nephron Development in Zebrafish

Abstract

The nephron is the functional unit of the kidney and comprises a blood filter lined by podocytes, proximal and distal tubules, and a collecting duct. How these segments arise during development is not understood. The zebrafish pronephros is ideal for studying segmentation, as it is anatomically simple, consisting of two nephrons. We have isolated 15 solute transporter genes that display segment‐restricted expression patterns. Our data indicates that contrary to current belief, the pronephros is organized into 8 segments and contains mostly tubule rather than duct epithelium. We next examined embryos deficient in retinoic acid (RA), a known regulator of nephrogenesis. Treating embryos with DEAB, an RA antagonist, inhibited the formation of podocytes and proximal tubule segments and expanded distal fates. From a time‐course analysis we found that RA is required at multiple stages to pattern the nephron. To explore how RA induces podocytes, we examined the expression of foxc1a, a transcription factor implicated in podocyte biology. Expression of foxc1a was lost in DEAB‐treated embryos, and knockdown of foxc1a in wild‐types led to a downregulation of various podocyte genes including the transcription factors wt1 and mafb, and components of the slit‐diaphragm filtration barrier. Our findings suggest that nephron segmentation is regulated by RA and that a RA‐foxc1a pathway is important for inducing podocytes.