Prostaglandin signaling regulates nephron segment patterning of renal progenitors during zebrafish kidney development

Abstract

Kidney formation involves patterning events that induce renal progenitors to form nephrons with an intricate composition of multiple segments. Here, we performed a chemical genetic screen using zebrafish and discovered that prostaglandins, lipid mediators involved in many physiological functions, influenced pronephros segmentation. Modulating levels of prostaglandin E2 (PGE2) or PGB2 restricted distal segment formation and expanded a proximal segment lineage. Perturbation of prostaglandin synthesis by manipulating Cox1 or Cox2 activity altered distal segment formation and was rescued by exogenous PGE2. Disruption of the PGE2 receptors Ptger2a and Ptger4a similarly affected the distal segments. Further, changes in Cox activity or PGE2 levels affected expression of the transcription factors irx3b and sim1a that mitigate pronephros segment patterning. These findings show for the first time that PGE2 is a regulator of nephron formation in the zebrafish embryonic kidney, thus revealing that prostaglandin signaling may have implications for renal birth defects and other diseases.DOI: http://dx.doi.org/10.7554/eLife.17551.001

The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development

“…During zebrafish embryogenesis, mesenchymal renal progenitors undergo an epithelial transition to form initially linear pronephric tubules by 24 hpf (Gerlach and Wingert, 2014; McKee et al, 2014). Thus, we used a riboprobe to label cells expressing cdh17 , which is expressed throughout the tubule and duct of the pronephros at 24 hpf, along with a ribroprobe designed to detect wt1b transcripts, to label podocytes, and then measured absolute tubule length from the rostral to caudal extent (Poureetezadi et al, 2016). Compared to WT embryos, the zep-/- developed tubules that were statistically the same length, while they lacked bilateral clusters of wt1b+ expressing cells as we had observed previously (Figure 3A,B).…”

Prostaglandins in the pathogenesis of kidney diseases

“…It is commonly recognized that COX-1 serves a constitutive housekeeping role [ 18 ]. Evidence has shown that COX-1 could regulate nephron formation via PGE2 in the zebrafish embryonic kidney [ 19 ]. COX-1 is also responsible for maintaining basic physiological functions including cytoprotection of the gastric mucosa and platelet aggregation [ 20 , 21 ].…”

ppargc1a controls nephron segmentation during zebrafish embryonic kidney ontogeny

“…Additionally, genetic studies in zebrafish are readily performed using reverse approaches like genome editing, knockdown or various overexpression techniques, as well as forward approaches like chemical genetics. Recently, we reported the results from a novel small molecule screen using the zebrafish pronephros as a segmentation model, which included the discovery that modulators of peroxisome proliferator-activated receptor (PPAR) signaling altered nephron segmentation ( Poureetezadi et al, 2016 ). Until the present study, however, the functions of discrete PPAR signaling components during nephrogenesis have remained unknown.…”

“… 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 ppargc1a directs renal progenitor fate.…”