Loss of Polycystin-1 Inhibits Bicc1 Expression during Mouse Development

Abstract

Bicc1 is a mouse homologue of Drosophila Bicaudal-C (dBic-C), which encodes an RNA-binding protein. Orthologs of dBic-C have been identified in many species, from C. elegans to humans. Bicc1-mutant mice exhibit a cystic phenotype in the kidney that is very similar to human polycystic kidney disease. Even though many studies have explored the gene characteristics and its functions in multiple species, the developmental profile of the Bicc1 gene product (Bicc1) in mammal has not yet been completely characterized. To this end, we generated a polyclonal antibody against Bicc1 and examined its spatial and temporal expression patterns during mouse embryogenesis and organogenesis. Our results demonstrated that Bicc1 starts to be expressed in the neural tube as early as embryonic day (E) 8.5 and is widely expressed in epithelial derivatives including the gut and hepatic cells at E10.5, and the pulmonary bronchi at E11.5. In mouse kidney development, Bicc1 appears in the early ureteric bud and mesonephric tubules at E11.5 and is also expressed in the metanephros at the same stage. During postnatal kidney development, Bicc1 expression gradually expands from the cortical to the medullary and papillary regions, and it is highly expressed in the proximal tubules. In addition, we discovered that loss of the Pkd1 gene product, polycystin-1 (PC1), whose mutation causes human autosomal dominant polycystic kidney disease (ADPKD), downregulates Bicc1 expression in vitro and in vivo. Our findings demonstrate that Bicc1 is developmentally regulated and reveal a new molecular link between Bicc1 and Pkd1.

The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes

“…On the basis of our observation of decreased PC2 expression and activated β-catenin signaling mediated by DVL2 in ANKS6 I747N kidneys, we speculate that impaired accessibility of BICC1 trapped by ANKS6 I747N molecule could lead to its defective function causing cyst formation. Proximal tubules express BICC1 35 and never develop cysts in ANKS6 I747N kidneys, further suggesting that ANKS6 and BICC1 are linked by an unidentified protein complex 15 also involved in cystogenesis. Of note, BICC1 and ANKS6 colocalized in the glomerulus, and there are glomerular cysts in Bicc1 mutant mice, 14,29 as well as in our ANKS6 I747N model of PKD.…”

The two-pore channel TPC1 is required for efficient protein processing through early and recycling endosomes

“…Co-staining with Lotus tetragonolobus lectin identified proximal tubule cells with the highest expression level of TPC1 (Fig. 6a ) 38 , 39 . Then, cortical sections from kidneys were co-stained with anti-TPC1 and anti-syntaxin-12 antibodies.…”

Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease

“…The functions of samcystin and fibrocystin are incompletely understood. Samcystin interacts with Bicc1 (72), which is an RNA-binding protein that localizes and silences bound mRNA (73) and acts both downstream and upstream of the polycystins (74,75), the proteins affected in human ADPKD. Fibrocystin, which is mutated in human ARPKD, colocalizes with the polycystins on primary cilia, physically interacts with polycystin-2 (76), and has been shown to regulate mTOR activity (77), similar to polycystin-1 (32).…”