Role of Bicaudal-C in Left-Right Axis Formation and Kidney Morphogenesis
The KH domain RNA binding protein Bicaudal-C is known to play a role in anterior-posterior (AP) patterning in Drosophila by acting on oskar mRNA. In mammals, its expression is induced at late gastrulation in the mesodermal layer of the ventral node. Renal cysts arise in mice and frogs lacking Bicaudal-C. Polycystic diseases and left-right (LR) axis malformations are frequently linked to cilia defects. However, a role for BicC in cilia function has not been demonstrated. Here, I report that targeted inactivation of BicC confirms a role in inducing polycystic kidney disease (PKD). In addition, this targeted mutation was found to randomize left-right (LR) asymmetry by disrupting the planar alignment of motile cilia required for cilia-driven fluid flow. Furthermore, depending on its SAM domain, BicC can uncouple Dvl2 signaling from the canonical Wnt pathway, which has been implicated in antagonizing planar cell polarity (PCP). The SAM domain is shown to concentrate BicC in cytoplasmic structures harboring RNA-processing bodies (P-bodies) and Dvl2. P-bodies are implicated degrading target mRNAs that are silenced by microRNAs. These results suggest a model whereby BicC links the orientation of cilia to PCP, possibly by regulating RNA silencing in P-bodies. In the kidney, BicC is localized in proximal tubules. The cystic phenotype is accompanied by increased levels of cAMP and of Adcy6 protein. BicC is proposed to inhibit target mRNA at the translation-initiation stage by regulating the assembly of miRNP/P-bodies.
Keywords: Bicaudal-C ; PKD ; Primary cilia ; directional flow ; Wnt ; PCP ; SAM domain ; K-homology ; cAMP ; Adcy6 ; Bicaudal-C ; Maladie Polykystique des Reins ; Cil Primaire ; Flux Nodal ; Wnt ; Polarité Planaire ; Domaine SAM ; Domaine KH ; AMPc ; Adénylate CyclaseThèse École polytechnique fédérale de Lausanne EPFL, n° 4668 (2010)
Programme doctoral Biologie moléculaire du cancer et de l'infection
Faculté des sciences de la vie
Institut suisse de Recherche Expérimentale sur le Cancer
Unité du Prof. Constam
Record created on 2010-02-22, modified on 2016-08-08