Mechanisms of nephrogenesis revealed by zebrafish chemical screen: Prostaglandin signaling modulates nephron progenitor fate

Abstract

Nephron development involves the creation of discrete segment populations that are specialized to fulfill unique physiological roles. As such, renal function is reliant on the proper execution of segment patterning programs. Despite the central importance of nephron segmentation, the genetic mechanisms that regulate this process are far from understood, in large part due to the experimental complexities and cost of interrogating these events in the mammalian metanephros. For this reason, forward genetics utilizing phenotypic screening in the zebrafish pronephros provides an avenue to gain novel insights about the mechanisms of nephron segmentation in the vertebrate kidney. Discoveries from zebrafish can highlight possible conserved pathways and provide a useful starting point for reverse genetic analyses with other animal models or in vitro approaches. In this review, we discuss the results of a novel chemical screen using the zebrafish to identify segmentation regulators. Through this screen, we identified for the first time that prostaglandin signaling can modulate nephron segmentation, and that it is normally requisite during development to mitigate segment fate choice in the embryonic kidney. We briefly discuss how these discoveries relate to current knowledge about nephron segmentation. Finally, we explore the possible implications of these findings for understanding renal ontogeny and disease, and how this knowledge may be useful for ongoing research initiatives that are aimed at deciphering how to build or rebuild the human kidney.