Esrrγ Regulates Nephron and Cilia Development by Modulating Prostaglandin Synthesis

Abstract

Vertebrate kidney development is a conserved and nuanced process that requires a complex concert of signals to facilitate patterning and differentiation of nephron functional units. Each nephron is comprised of over a dozen specialized cell types, characterized by the expression of solute transporters and other distinct cellular features such as the formation of cilia, which are hair-like projections that facilitate mechano- and chemo-sensing. Since deficiency of the transcription factor Esrrγ has been linked to kidney dysfunction, typified by cyst formation and kidney failure, we hypothesize that Esrrγ also plays a role during renal ontogeny. Zebrafish offer a distinct model to study organogenesis, as highly conserved nephrons are fully formed by 24 hours post fertilization (hpf), and function beginning at 48 hpf. Zebrafish nephrons are comprised of both mono- and multi- ciliated cells, further aiding in the study of cilia formation. Using this conserved zebrafish model, we found that esrrγa regulates both nephron cell specification and ciliogenesis. esrrγa deficient embryos exhibited altered nephron composition with increased proximal segments, decreased distal segment populations and decreased number of multiciliated cells. Further, the formation of cilia was disrupted, where both cilia length and number of ciliated basal bodies were significantly reduced in mono- and multi- ciliated cell types. Cilia formation was disrupted in a non-tissue specific manner, as cilia length was also decreased in the Kupffer's vesicle at 14 hpf, and the ear structure at 96 hpf. These phenotypes were consistent with a disruption of prostaglandin signaling, and we found that expression of the prostaglandin cyclooxygenase enzyme (ptgs1) was reduced in esrrya deficient embryos. Treatment with dmPGE2 or ptgs1 overexpression was sufficient to rescue renal and cilia defects. These data position esrrγa as a key regulator of prostaglandin signaling and nephron cell development, and Esrrγ may be a potential target for future ciliopathic treatments. This study has far reaching implications, as cilia are key features of various tissues, including the kidney, reproductive system, central nervous system, and respiratory system.