Pharmacological cholesterol depletion disturbs ciliogenesis and ciliary function in developing zebrafish

Abstract

Patients with an inherited inability to synthesize sufficient amounts of cholesterol develop congenital malformations of the skull, toes, kidney and heart. As development of these structures depends on functional cilia we investigated whether cholesterol regulates ciliogenesis through inhibition of hydroxymethylglutaryl-Coenzyme A reductase (HMG-CoA-R), the rate-limiting enzyme in cholesterol synthesis. HMG-CoA-R is efficiently inhibited by statins, a standard medication for hyperlipidemia. When zebrafish embryos are treated with statins cilia dysfunction phenotypes including heart defects, left-right asymmetry defects and malformation of ciliated organs develop, which are ameliorated by cholesterol replenishment. HMG-CoA-R inhibition and other means of cholesterol reduction lowered ciliation frequency and cilia length in zebrafish as well as several mammalian cell types. Cholesterol depletion further triggers an inability for ciliary signalling. Because of a reduction of the transition zone component Pi(4,5)P2 we propose that cholesterol governs crucial steps of cilium extension. Taken together, we report that cholesterol abrogation provokes cilia defects.