Abstract
Ciliopathies are a diverse group of disorders resulting from abnormalities in the development or function of multiple organs. While significant research has clarified the role of the primary cilium in transducing numerous signalling pathways, elucidating causes of neuronal and skeletal development disorders, the origins of other ciliopathy-related conditions, such as hepatic fibrocystic diseases, remain elusive. Additionally, attempts to correlate specific ciliary proteins with distinct phenotypes have been largely unsuccessful due to the variable and overlapping symptoms of ciliopathies. This study aims to elucidate the extraciliary roles of the protein B9D2 in the development of biliary dysgenesis, a condition present in Meckel-Gruber and Joubert syndromes caused by mutations in this protein. Traditionally, B9D2 is known for its role at the transition zone of the primary cilium in the transduction of signalling pathways notably Wingless and Hedgehog. Our work demonstrates that before ciliogenesis occurs, B9D2 is crucial for the maturation and maintenance of tight junctions ensuring epithelial barrier tightness and appropriate biliary lumen formation. This study provides new insights into the mechanisms underlying biliary dysgenesis in hepatic ciliopathies, suggesting that further exploration of the non-ciliary functions of proteins involved in ciliopathies could lead to a better understanding and treatment of these complex disorders.