Abstract
Bardet-Biedl syndrome (BBS) and nephronophthisis (NPH) are hereditary autosomal recessive disorders, encoded by two families of diverse genes. BBS and NPH display several overlapping phenotypes including cystic kidney disease, retinitis pigmentosa, liver fibrosis, situs inversus and cerebellar defects. Since most of the BBS and NPH proteins localize to cilia and/or their appendages, BBS and NPH are considered ciliopathies. In this study, we characterized the function of the transcription factor Nphp7 in zebrafish, and addressed the molecular connection between BBS and NPH. The knockdown of zebrafish bbs1 and nphp7.2 caused similar phenotypic changes including convergent extension defects, curvature of the body axis, hydrocephalus, abnormal heart looping and cystic pronephros, all consistent with an altered ciliary function. Immunoprecipitation assays revealed a physical interaction between BBS1 and NPHP7, and the simultaneous knockdown of zbbs1 and znphp7.2 enhanced the cystic pronephros phenotype synergistically, suggesting a genetic interaction between zbbs1 and znphp7.2 in vivo. Deletion of zBbs1 or zNphp7.2 did not compromise cilia formation, but disrupted cilia motility. Although NPHP7 has been shown to act as transcriptional repressor, our studies suggest a crosstalk between BBS1 and NPHP7 in regulating normal function of the cilium.
Highlights
Autosomal recessive cystic kidneys are typically part of complex syndromes involving multiple organs
Protein families, we tested the interaction between NPHP7 and the Bardet-Biedl syndrome (BBS) family members BBS1-12, using tagged versions of human proteins overexpressed in human embryonic kidney (HEK) 293T cells
Since BBS1 has been characterized as a component of the BBSome, involved in ciliary transport processes, we decided to clarify the role of the BBS1/NPHP7 complex
Summary
Autosomal recessive cystic kidneys are typically part of complex syndromes involving multiple organs. Since most gene products mutated in these syndromes localize to the cilium, an abnormal function of the cilium has been implicated in their pathogenesis. The primary cilium is thought to function as a mechano- and/or chemosensor, which detects signals from extracellular environment and transmits them to the inside of the cell. Mutations of numerous ciliary proteins lead to structurally or functionally abnormal cilia [1]. The primary cilium is involved in important signalling cascades such as Hedgehog, Wnt, planar cell polarity, and calcium-dependant signalling pathways [3]. Cilia-related cystic kidney diseases include autosomal dominant as well as recessive polycystic kidney disease, including the Bardet–Biedl syndrome (BBS) and nephronophthisis (NPH) [4]
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