Disruption of Intraflagellar Transport in Adult Mice Leads to Obesity and Slow-Onset Cystic Kidney Disease

Abstract

The assembly of primary cilia is dependent on intraflagellar transport (IFT), which mediates the bidirectional movement of proteins between the base and tip of the cilium. In mice, congenic mutations disrupting genes required for IFT (e.g., Tg737 or the IFT kinesin Kif3a) are embryonic lethal, whereas kidney-specific disruption of IFT results in severe, rapidly progressing cystic pathology. Although the function of primary cilia in most tissues is unknown, in the kidney they are mechanosenstive organelles that detect fluid flow through the tubule lumen. The loss of this flow-induced signaling pathway is thought to be a major contributing factor to cyst formation. Recent data also suggest that there is a connection between ciliary dysfunction and obesity as evidenced by the discovery that proteins associated with human obesity syndromes such as Alström and Bardet-Biedl localize to this organelle. To more directly assess the importance of cilia in postnatal life, we utilized conditional alleles of two ciliogenic genes (Tg737 and Kif3a) to systemically induce cilia loss in adults. Surprisingly, the cystic kidney pathology in these mutants is dependent on the time at which cilia loss was induced, suggesting that cyst formation is not simply caused by impaired mechanosensation. In addition to the cystic pathology, the conditional cilia mutant mice become obese, are hyperphagic, and have elevated levels of serum insulin, glucose, and leptin. We further defined where in the body cilia are required for normal energy homeostasis by disrupting cilia on neurons throughout the central nervous system and on pro-opiomelanocortin-expressing cells in the hypothalamus, both of which resulted in obesity. These data establish that neuronal cilia function in a pathway regulating satiety responses.

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

“…[24][25][26][27] Finally, consistent with this finding, recent evidence in ciliopathies has linked obesity to the regulation of homeostasis within the hypothalamus. 28 Our zebrafish and MEF experiments indicate that the Y86C missense variant identified in this study is hypomorphic, as overexpression of Y86C cDNA is not efficient in rescuing the arl13b sco zebrafish and Arl13b hnn MEF phenotypes. The early lethality of the Arl13b hnn mouse indicates a critical role for ARL13B in early embryonic development.…”

Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons

“…Conditional disruption of Ift88 is a well established method for ablating cilia in a cell-type-specific manner (51) and has been effectively used to disrupt cilia on central neurons (32)(33)(34). Although we saw a complete lack of Kiss1r-positive cilia in adult GnRH cilia-mice, the fact that GnRH neurons are not positive for any canonical ciliary markers prevented us from validating the loss of cilia structure.…”

Present Status and Advances in Autosomal Dominant Polycystic Kidney Disease

“…Growth and maintenance of primary cilia relies on the Intraflagellar Transport (IFT) system [49,50], which transports various proteins to and from cilia, including polycystin-1 and polycystin-2, via kinesin and dynein [51][52][53]. Thus, besides the absence of polycystins that leads to polycystic kidney disease phenotype, IFT system deletions such as deactivating the IFT system components Kif3a, Ift20 and Ift88 in mouse models also cause polycystic kidney disease phenotype [54]. Although cilia loss is associated with cystic kidney disease, recent studies have shown that there is no evidence of primary cilia-associated Ca 2+ influx in both the renal tubules and cell lines stimulated by fluid flow at physiological levels [55].…”