|Budget Amount *help
¥12,100,000 (Direct Cost: ¥12,100,000)
Fiscal Year 2002: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 2001: ¥7,000,000 (Direct Cost: ¥7,000,000)
The ERM family consists of three closely-related proteins, ezrin, radixin, and moesins, which function as general cross-linkers between actin filaments and integral membrane proteins. Here, we generated mice lacking radixin (gene symbol RDX), which is the dominant ERM protein in the wildtype liver, and is concentrated at bile canalicular membranes (BCMs). Rdx^<-1-> mice were normal at birth, but around 4 weeks of age, the serum levels of conjugated bilirubin began to increase gradually without showing any histological abnormality; after 8 weeks of age, mild liver injury was observed. This phenotype is similar to human conjugated hyperbilirubinemia in Dubin-Johnson syndrome, which is caused by mutations in the multi-drug resistance protein 2 (Mrp2, gene symbol ABCC2), although this syndrome is not associated with overt liver injury. In wildtype mice, Mrp2 is concentrated at BCMs to secrete conjugated bilirubin into bile. From birth in Rdx^<-1-> mice, Mrp2 appeared to be selectively decreased (down to 〜20%) in BCMs compared to other BCM proteins such as dipeptidyl peptidase IV(CD26) and P-glycoproteins (down to 〜70%). Furthermore, several lines of evidence have shown a direct association of radixin with the C-terminal cytoplasmic domain of Mrp2. These findings indicate that radixin is required for conjugated bilirubin secretion through its support of Mrp2 localization at BCMs. This study provides new insights into the molecular mechanisms of bile secretion and conjugated hyperbilirubinemia, and the involvement of ERM proteins in determining the localization of integral membrane proteins.