Analysis of the Genetic and Molecular Mechanisms That Regulate Renal Progenitor Cell Fate Specification

Kidney disease is the 9^th leading cause of death in the United States alone and can arise at any stage in life (American Kidney Fund, 2017). During development, congenital anomalies of the kidney and urinary tract (CAKUT) includes a broad spectrum of malformations that can be as severe as agenesis, which is when one or both kidneys fail to develop. Significantly, 20-30% of all prenatally identified anomalies can be categorized as CAKUT, and in extreme cases, this type of condition can lead to renal failure or the premature death of the fetus. Alternately, once the kidney is fully formed, it can undergo insults resulting in acute kidney injury (AKI). While it has been documented that a limited degree of regeneration can occur after AKI, continued damage to the kidney will lead to end stage renal disease (ESRD), ultimately requiring a lifetime of dialysis or a kidney transplant for survival. Even so, regardless of the developmental or post-natal origins of kidney disease, the commonality of these debilitating states is dysfunction of the nephrons, which are the functional units of the kidney (McCampbell and Wingert, 2012). Each nephron is characterized by a blood filter connected to an epithelial tubule consisting of a series of proximal and distal segments that are responsible for the essential tasks of the kidney, including nutrient reabsorption and pH regulation. Consequently, our overarching goal is to delineate the genetic and molecular mechanisms that regulate the specification of these renal epithelial cells as a means to better understand how these pathways can go awry and result in kidney disease. Here, we reveal novel roles for the conserved sim1a and irx2a/3b transcription factors during nephrogenesis using the zebrafish as a vertebrate model of development. In general, we discovered that sim1a and irx2a control the formation of the proximal straight tubule (PST) lineage, while irx2a/3b participate in the modulation of multiciliated cell (MCC) fates. These findings not only enhance our current knowledge of the transcriptional cascade that directs renal ontogeny, but also provide broader implications for CAKUT and the development of cell therapies through reprogramming.