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.
Highlights
Studies of animal mutant models for polycystic kidney disease (PKD) and of human PKD patients have identified more than 20 genes whose mutations can induce PKD phenotypes [1,2,3]
The,110-kD Bicc1 band was readily detected in wildtype inner medullary collecting duct (IMCD) cells and highly strong band was showed in the IMCDBicc1 cells, whereas almost no band was seen in the IMCDshC4C cells (Fig. 1D– E)
Studies using chemically-induced or natively occurring Bicc1mutant mouse models and other Bicc1-gene-targeted mouse models have recently demonstrated that the disruption of Bicc1 can induce polycystic kidney disease with phenotypes very similar to human autosomal dominant polycystic kidney disease (ADPKD) [5,6,17]
Summary
Studies of animal mutant models for polycystic kidney disease (PKD) and of human PKD patients have identified more than 20 genes whose mutations can induce PKD phenotypes [1,2,3]. The continued study of these cyst-associated genes and their products will help elucidate the disease mechanism of human inherited polycystic kidney diseases, such as autosomal dominant and recessive PKD (ADPKD and ARPKD). Bicc is a mouse homologue of Drosophila Bicaudal-C (dBic-C), the orthologs of which are much conserved in many species, from C. elegans to humans [4,5,6,7,8]. Loss of dBic-C in Drosophila disrupts the direction of anterior follicle cell migration and affects anteriorposterior patterning, so that the resulting embryos lack heads and exhibit duplicated posterior segments instead [9,10]. Knockdown of the zebrafish homologue of Bicaudal-C (zBic-C) induces cystic kidneys in vivo [12]
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