Bicaudal C, a novel regulator of Dvl signaling abutting RNA-processing bodies, controls cilia orientation and leftward flow

Abstract

Polycystic diseases and left-right (LR) axis malformations are frequently linked to cilia defects. Renal cysts also arise in mice and frogs lacking Bicaudal C (BicC), a conserved RNA-binding protein containing K-homology (KH) domains and a sterile alpha motif (SAM). However, a role for BicC in cilia function has not been demonstrated. Here, we report that targeted inactivation of BicC randomizes 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 concentrates BicC in cytoplasmic structures harboring RNA-processing bodies (P-bodies) and Dvl2. These results suggest a model whereby BicC links the orientation of cilia with PCP, possibly by regulating RNA silencing in P-bodies.

BICC1 Expression is Elevated in Depressed Subjects and Contributes to Depressive Behavior in Rodents

“…For example, overexpression of BICC1 resulted in co-immunoprecipitation with par-1, Cp190, Cip4, Klp10A, Rho-GAP18B, and CG17293, which are all suggested or known to have roles in cytoskeletal regulation (Chicoine et al, 2007) and could potentially affect synaptic plasticity, which is disrupted by chronic stress and depression (Li et al, 2011;Liu and Aghajanian, 2008). Previous work has also shown that BICC1, via its SAM domain, can block Wnt signaling (Kraus et al, 2012) by uncoupling disheveled-2 signaling from the canonical Wnt pathway (Maisonneuve et al, 2009). The Wnt pathway has been implicated in the pathophysiology of depression (Voleti et al, 2011), suggesting another potential mechanism by which BICC1 could regulate MDD.…”

“…BICC1 is an RNA-binding protein that plays a role in cytoskeletal organization and cellto-cell communication (Chicoine et al, 2007;Mahone et al, 1995;Snee and Macdonald, 2009). Further, via its sterile alpha motif (SAM) domain, BICC1 can block Wnt signaling (Kraus et al, 2012), a pathway implicated in the pathophysiology of depression (Voleti et al, 2011), by uncoupling disheveled-2 signaling from the canonical Wnt pathway (Maisonneuve et al, 2009). BICC1 is well-studied in the context of development (Maisonneuve et al, 2009) and polycystic kidney disease (Guay-Woodford, 2003), but there have been few studies of BICC1 in the brain.…”

Fluid flow and interlinked feedback loops establish left–right asymmetric decay of Cerl2 mRNA

“…Nodal flow is generated by clockwise rotation of multiple cilia that are positioned at the posterior side of node cells by the planar cell polarity pathway [2][3][4] , and it promotes asymmetric gene expression around the node. The first gene to show asymmetric expression around the node is that for Cerl2 (Cerberus-like protein 2), which is expressed in perinodal crown cells in a LoR manner and has a key role in L-R determination as an inhibitor of the protein Nodal 5,6 .…”

Mutations in ANKS6 Cause a Nephronophthisis-Like Phenotype with ESRD

“…[24][25][26] The canonical b-catenin pathway and the planar cell polarity pathway recently received attention for their roles in multiple cellular processes within the kidney. 27 It has been demonstrated that both overactivation and inactivation of the canonical Wnt pathway lead to cystic renal phenotypes, [28][29][30] suggesting that the Wnt/b-catenin system must be delicately balanced in the kidney to prevent cyst formation. Bicc1 is known to regulate Dishevelled signaling 29 and mutations in BICC1 were reported to cause cystic renal dysplasia in humans that is associated with hyperactivation of the Wnt pathway.…”

“…27 It has been demonstrated that both overactivation and inactivation of the canonical Wnt pathway lead to cystic renal phenotypes, [28][29][30] suggesting that the Wnt/b-catenin system must be delicately balanced in the kidney to prevent cyst formation. Bicc1 is known to regulate Dishevelled signaling 29 and mutations in BICC1 were reported to cause cystic renal dysplasia in humans that is associated with hyperactivation of the Wnt pathway. 30 Hoff et al 18 recently reported that ANKS6 affects the function of NPHP2/inversin(INVS),another regulator of Dishevelled and Wnt signaling.…”