Abstract
The genetic regulation of nephron patterning during kidney organogenesis remains poorly understood. Nephron tubules in zebrafish are composed of segment populations that have unique absorptive and secretory roles, as well as multiciliated cells (MCCs) that govern fluid flow. Here, we report that the transcription factor iroquois 2a (irx2a) is requisite for zebrafish nephrogenesis. irx2a transcripts localized to the developing pronephros and maturing MCCs, and loss of function altered formation of two segment populations and reduced MCC number. Interestingly, irx2a deficient embryos had reduced expression of an essential MCC gene ets variant 5a (etv5a), and were rescued by etv5a overexpression, supporting the conclusion that etv5a acts downstream of irx2a to control MCC ontogeny. Finally, we found that retinoic acid (RA) signaling affects the irx2a expression domain in renal progenitors, positioning irx2a downstream of RA. In sum, this work reveals new roles for irx2a during nephrogenesis, identifying irx2a as a crucial connection between RA signaling, segmentation, and the control of etv5a mediated MCC formation. Further investigation of the genetic players involved in these events will enhance our understanding of the molecular pathways that govern renal development, which can be used help create therapeutics to treat congenital and acquired kidney diseases.
Highlights
The vertebrate kidney is an architecturally intricate organ composed of nephron functional units that cleanse the circulation of metabolic waste and maintain fluid homeostasis[1]
This is due to the complicated nature of kidney organogenesis, which involves the coordinated creation of nephrons that each contains a multitude of differentiated cell types in precise arrangements
The present work has enhanced our understanding of the renal transcription factor code that currently defines the zebrafish pronephros by defining several essential roles of irx2a within the regulatory networks that guide renal progenitor fate decisions (Fig. 7)
Summary
The vertebrate kidney is an architecturally intricate organ composed of nephron functional units that cleanse the circulation of metabolic waste and maintain fluid homeostasis[1]. The epithelial tubule of the nephron is subdivided into functional regions known as the proximal convoluted and straight tubule segments (PCT, PST) and the distal early and late (DE, DL) segments, the latter where the associated corpuscle of Stannius (CS) gland arises[16] Each of these segments is comprised of unique differentiated transporter cells that possess a single primary cilium, which is a microtubule-based projection that extends from the apical surface into the extracellular space. While MCCs are a major renal epithelial cell type in zebrafish, analogous MCCs in humans have only been documented in the fetal kidney[26,27] and in case reports of kidney diseases such as hypercalcemia, congenital nephrosis and glomerulonephritis[27,28,29,30,31,32,33,34] These findings suggest that understanding the mechanisms that guide MCC formation may provide insights about kidney development and disease. The exact mechanisms that direct the specification of MCC remains are not yet completely elucidated
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