New Ciliopathies Mouse Model Identification And The Disease Mechanism Study

Primary cilium is a microtubule-based organelle that protrudes from the basal body and emanates from the surface of many types of eukaryotic cells.It involves in regulating both movement and signaling transduction,which is important for the embryo development and normal organ functions.The structure or function deficiency of primary cilia causes ciliopathies.Cystic kidney is the common clinical features for many ciliopathies.Its treatment has been a major clinical problem,but also the focus of research in the kidney field.Here,we found that the offspring of CAGGS-SB10 trangene mice display two thrums phenotypes with Mendelian ratio.We identified that this trangene insection caused a-3kb deletion in the intron 12 of Sclt1 gene.The deletion of Sclt1 gene caused the absence of cilia formation in the renal epithelial cells,as well as increased kidney weight and size,with cysts fulfilled the kidney and renal function failure.The mice have very highly penetrance of neonatal lethal,only 5%of mutant mice can survive until 21 days.In addition,the Sclt1-/-micc also have oral cleft,short intestine,skeletal and testis abnormalities.SCLT1 is an adapter protein that links clathrin and SCN10A(sodium voltage-gated channel alpha subunit 10).It is also one of the centriole distal appendage proteins,which facilitates the docking of the mother centriole to the plasma membrane to promote cilia initiation.We used RNA-seq,western blot and immuohistochemistry experiments to explore the molecular mechanisms underlying the development of the cystic kidney in the Sclt1-/-mice.We found that Scltl deletion activated STAT3,PKA/ERK and TGF-β/SMAD signaling pathways,which led to proliferation and apoptosis of renal tubule epithelial cells,as well as increased inflammation and fibrosis,finally caused cysts formation.Pyrimethamine(SATA3 inhibitor)treatment significantly reduced the kidney weight and cysts number and area in the Sclt1-/-mice.Moreover,pyrimethamine treatment also prolonged the intestine length of Sclt1-/-mice.These rescued phenotypes may cause by the inhibition of STAT3,that decreased the hyperproliferation and inflammation of renal tubule epithelial cells.Overall,our results suggest that SCLT1 is an important regulator for the kidney development.The Sclt1-/-mice provide a new animal model to the study of the patho-mechanisms of ciliopathies.STAT3 inhibition may be a promising target for SCLT1-associated cystic kidney and other related ciliopathies.