Loss of cilia causes embryonic lung hypoplasia, liver fibrosis and cholestasis in the talpid3 ciliopathy mutant

Sonic hedgehog plays an essential role in maintaining hepatoblasts in a proliferative non-differentiating state during embryogenesis. Transduction of the Hedgehog signaling pathway is dependent on the presence of functional primary cilia and hepatoblasts, therefore, must require primary cilia for normal function. In congenital syndromes in which cilia are absent or non-functional (ciliopathies) hepatorenal fibrocystic disease is common and primarily characterized by ductal plate malformations which underlie the formation of liver cysts, as well as less commonly, by hepatic fibrosis, although a role for abnormal Hedgehog signal transduction has not been implicated in these phenotypes. We have examined liver, lung and rib development in the talpid3 chicken mutant, a ciliopathy model in which abnormal Hedgehog signaling is well characterized. We find that the talpid3 phenotype closely models phenotype of human short-rib polydactyly syndromes which are caused by the loss of cilia, including hypoplastic lungs and liver failure. Through an analysis of liver and lung development in the talpid3 chicken, we propose that cilia in the liver are essential for the transduction of Hedgehog signaling during hepatic development. The talpid3 chicken represents a useful resource in furthering our understanding of the pathology of ciliopathies beyond the treatment of thoracic insufficiency as well as generating insights into the role Hedgehog signaling in hepatic development.