Abstract
Vertebrate kidneys contain nephron functional units where specialized epithelial cell types are organized into segments with discrete physiological roles. Many gaps remain in our understanding of how segment regions develop. Here, we report that the transcription factor empty spiracles homeobox gene 1 (emx1) is a novel nephron segment regulator during embryonic kidney development in zebrafish. emx1 loss of function altered the domains of distal segments without changes in cell turnover or traits like size and morphology, indicating that emx1 directs distal segment fates during nephrogenesis. In exploring how emx1 influences nephron patterning, we found that retinoic acid (RA), a morphogen that induces proximal and represses distal segments, negatively regulates emx1 expression. Next, through a series of genetic studies, we found that emx1 acts downstream of a cascade involving mecom and tbx2b, which encode essential distal segment transcription factors. Finally, we determined that emx1 regulates the expression domains of irx3b and irx1a to control distal segmentation, and sim1a to control corpuscle of Stannius formation. Taken together, our work reveals for the first time that emx1 is a key component of the pronephros segmentation network, which has implications for understanding the genetic regulatory cascades that orchestrate vertebrate nephron patterning.
Highlights
Ontogeny of the vertebrate kidney is a dynamic process involving the sequential formation and regression of multiple structures from the intermediate mesoderm (IM) during embryogenesis[1]
Emx[1] encodes a homeodomain transcription factor that is expressed in renal progenitors during early stages of zebrafish pronephros development[27], and numbers among those genes that have been implicated to act downstream of retinoic acid (RA) signaling during nephron segmentation20. emx[1] is related to the fruitfly gene empty spiracles[28], which controls the formation of anterior head segments and the development of the olfactory system[29,30]
The segment volume to length ratio or the number of nuclei in a given area was not significantly different between emx[1] deficient and WT control embryos in the DE or DL (Fig. 4F,G). These analyses indicate that the expanded DE and reduced DL are not related to changes in cell dimension or arrangement differences
Summary
Ontogeny of the vertebrate kidney is a dynamic process involving the sequential formation and regression of multiple structures from the intermediate mesoderm (IM) during embryogenesis[1] These developmental events can encompass up to three renal forms, termed the pronephros, mesonephros, and metanephros, that share a composition of nephron subunits in various anatomical arrangements[1]. RA promotes proximal segment identities and inhibits distal ones through patterning events that transpire during pre-gastrula and gastrula stages[19,20,24] and lead to alterations in the expression domains of key transcription factors that include irx3b20, mecom[22], tbx2a/b23, sim1a25, and etv5a26. Emx[1] encodes a homeodomain transcription factor that is expressed in renal progenitors during early stages of zebrafish pronephros development[27], and numbers among those genes that have been implicated to act downstream of RA signaling during nephron segmentation. Despite their intriguing expression patterns during vertebrate nephrogenesis, the function of emx1/Emx[1] during nephron ontogeny has not been examined
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