Scaling Up to Study Kidney Development: Using the Zebrafish as a High-Throughput Model to Identify Novel Genetic Regulators

Chronic kidney disease (CKD), though not reported on much in the media, is a disease that kills more Americans every year than breast or prostate cancer (NIDDK). In fact, almost 14% of the American population is currently suffering from CKD (NIDDK). At present, there are few avenues for treatment and almost no way to reverse this damage. One of the limiting factors for developing new treatments to kidney disorders is a lack of knowledge about the pathways utilized to develop this cellularly diverse organ. Specifically, there is little understanding about the development of the functional unit of the kidney, the nephron. Gaining this knowledge could continue the progress in the evolution of targeted therapeutics and organoid technology. Hampering this progress are the feasibility issues of mammalian-based studies. Fortunately, the embryonic zebrafish kidney, or pronephros, contains two nephrons that are genetically conserved to the adult human kidney. The studies of this work involve utilizing the advantages of the embryonic zebrafish kidney to identify novel regulators of nephrogenesis to fill the void in knowledge about the genetics of nephron development across vertebrates. This dissertation is a collective of several of those identified genetic regulators. We discovered that the tbx2a and tbx2b transcription factors promote the formation of the distal late (DL) segment and cooperatively with Notch inhibit the development of the corpuscle of Stannius (CS) gland. The factors osr1, brca2, and wnt2ba do no impact distal fates, but rather are critical for proximal lineages such as the podocytes. These findings improve what was previously known about the genetics of kidney development, which will be useful in the future avenues of diagnostics and targeted therapeutics.