Homeogene emx1 is required for nephron distal segment development in zebrafish

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.

Tfap2a is a novel gatekeeper of nephron differentiation during kidney development

“…Based on recent studies in the zebrafish model, upstream candidates for regulating tfap2a/2b may occupy the prostaglandin signaling pathway, which controls the balance of DE and DL territories during zebrafish nephrogenesis , or be transcription factors such as mecom, ppargc1a, tbx2a/2b or emx1, which regulate DL development Drummond et al, 2016;Chambers et al, 2018;Morales et al, 2018). Additional network candidates that may crosstalk with tfap2a/2b include sall1 and sox11.…”

ppargc1a controls nephron segmentation during zebrafish embryonic kidney ontogeny

“…Future efforts to identify these other genetic components are needed to decipher the mechanisms of PST formation, where there have been few advances in understanding the patterning of this segment despite progress in understanding ciliated cell fate choice in this pronephros region ( Marra et al, 2016 ). With respect to DL segment ontogeny, additional work is also needed to ascertain how ppargc1a relates to known DL regulators such as the transcription factors mecom , tbx2a , and emx1 along with prostaglandin signaling ( Li et al, 2014 ; Drummond et al, 2017 ; Poureetezadi et al, 2016 ; Morales et al, 2018 ).…”

Advances in understanding vertebrate nephrogenesis

“…86 One premiere system has been the zebrafish embryonic kidney, or pronephros, where a growing list of genes and signaling pathways has been identified. [104][105][106][107][108][109][110][111][112][113][114] Recent evidence from human kidneys strongly suggests potential conservation in gene expression and function with their zebrafish counterpart. 104,115 Combining the large data sets of mice and human scRNA sequencing with the relative ease of loss of function studies in zebrafish could streamline an evolutionarily conserved pipeline of essential factors for nephrogenesis.…”