Esrrγa regulates nephron development and ciliogenesis by controlling prostaglandin synthesis and cooperation with Ppargc1a

Abstract

AbstractCilia are essential for the ontogeny and function of many tissues, including the kidney. In mammals, Esrrγ has been previously established as a significant determinant of renal health, with decreased expression linked to age related dysfunction, cyst formation, and kidney disease. Here, we report that the Esrrγ vertebrate ortholog estrogen related receptor gamma a (esrrγa) is essential for proper cell fate choice within kidney functional units (nephrons) as well as ciliogenesis. Deficiency of esrrγa resulted in nephrons with alterations in proximodistal segmentation and a decreased multiciliated epithelial cell populace. Surprisingly, esrrγa deficiency disrupted renal ciliogenesis and caused a similar abrogation within the developing node and otic vesicle—all defects that occurred independently of changes in cell polarity or basal body organization. These phenotypes were consistent with interruptions in prostaglandin signaling, and we found that ciliogenesis was rescued in esrrγa deficient embryos with exogenous PGE2 or through overexpression of the cyclooxygenase enzyme Ptgs1. Through genetic interaction studies, we found that peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (ppargc1a), which acts upstream of Ptgs1-mediated prostaglandin synthesis, has a synergistic relationship with esrrγa in the ciliogenic pathway. These data position esrrγa as a novel link between ciliogenesis and nephrogenesis through regulation of prostaglandin signaling and cooperation with ppargc1a, and highlight esrrγa as a potential new target for future ciliopathic treatments.