Ppargc1a Controls Ciliated Cell Development by Regulating Prostaglandin Biosynthesis

Abstract

Cilia are microtubule-based organelles that function in a multitude of physiological contexts to perform chemosensing, mechanosensing, or fluid propulsion. The process of ciliogenesis is highly regulated and disruptions result in disease states termed ciliopathies. Here, we show novel roles for peroxisome proliferator-activated receptor gamma 1 alpha ( ppargc1a ) during ciliogenesis in nodal, mono-, and multiciliated cells (MCCs) as well as discernment of renal tubule ciliated cell fate during embryogenesis. We discovered that ppargc1a performs both roles by affecting prostaglandin signaling, where cilia formation and renal MCC fate were restored with prostaglandin E 2 (PGE 2 ) treatment. Genetic disruption of ppargc1a specifically reduced expression of the prostanoid biosynthesis gene prostaglandin-endoperoxide synthase 1 ( ptgs1 ), and suboptimal knockdown of both genes revealed a synergistic effect. Further, ptgs1 overexpression rescued ciliogenesis and renal MCCs in ppargc1a deficient embryos. These findings position Ppargc1a as an essential genetic regulator of prostaglandin signaling during ciliated cell ontogeny.

Keywords: cilia, kidney, nephron, differentiation, ppargc1a, ptgs1, prostaglandin, multiciliated cell, zebrafish