Ciliary dysfunction in adult mice results in slowly progressing cystic kidney disease and disrupts energy homeostasis

Abstract

Cilia are microtubule-based organelles that can be motile or immotile (primary) and they are present on nearly every cell in the body. Their assembly requires a highly conserved process called intraflagellar transport (IFT) which mediates bidirectional movement of protein complexes between the base and tip of the cilium. Although once thought of as a vestigial organelle, the primary cilium is now known to have essential sensory and signaling roles. Disruption of this organelle in mice results in embryonic lethality and is associated with defects in left-right body axis specification, neural tube closure and patterning, and altered digit formation in the limb bud. In part this is due to aberrant coordination of Shh, Wnt, and PDGFR-α signaling which require the cilium for normal regulation. In addition, impaired ciliary function is thought to be a causative factor in numerous disease phenotypes in mice and humans, such as retinitis pigmentosa, hydrocephalus, and cystic lesions in the kidney, liver, and pancreas. One function of the primary cilia is thought to be that of mechanosensor that detects fluid movement through the lumen of tubules or ducts. To better analyze the function of cilia in the absence of the severe developmental defects and lethality, we utilized conditional alleles of two IFT genes to induce cilia loss systemically in adult mice or in specific tissues. As expected, disruption of cilia throughout the body or in the kidney during late gestation or in the perinatal period resulted in a rapid onset and severe cystic kidney phenotype and death around weaning age. In contrast when cilia loss was induced systemically in 8 to 12 week old mice a pronounced cystic kidney phenotype was not evident until nearly a year after cilia were ablated. This unexpected outcome indicates that loss of cilia mediated mechanosensation in itself is not sufficient to cause cyst development. Possible mechanisms behind the delayed cyst formation in the adult induced mutants will be discussed. While the cystic kidney phenotype was greatly attenuated in the adult-induced mutants, we did uncover an additional role for cilia in regulating energy homeostasis as the conditional mutants became obese. The increased weight gain was due to hyperphagia and not to changes in activity or metabolism. Further analyses demonstrate that the obesity phenotype can be recapitulated by the loss of cilia on CNS neurons and more specifically by loss of cilia on proopiomelanocortin (POMC) neurons in the hypothalamus. These data suggest that primary cilia function as a sensory organelle involved in reception, transmission, or regulation of satiety signals, possibly involving the insulin or leptin signaling axis.