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

Charlotte Maisonneuve,Martin Blum,Philipp Vick,Tina Beyer,Philipp Andre,Daniel B. Constam,Thomas Weber,Isabelle Guilleret

doi:10.1242/dev.038174

Charlotte Maisonneuve, Martin Blum + Show 6 more

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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.

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In vertebrates, left-right (LR) asymmetry of the visceral situs is established by Nodal signals from the posterior notochord (PNC), known as the ventral node in mammals (Brennan et al, 2002; Levin et al, 1995), Kupffer’s vesicle in zebrafish, or the gastrocoel roof plate (GRP) in Xenopus (Essner et al, 2002; Schweickert et al, 2007)
Heterotaxia and randomization of asymmetric Nodal signaling in Bicc1–/– mice Using whole-mount in situ hybridization, we confirmed that mouse Bicc1 is induced throughout the PNC/ventral node between embryonic day (E) 7.5 and E8.5 (Wessely et al, 2001)
This study reveals a conserved role for Bicaudal C (BicC) in directing the planar orientation of cilia and leftward fluid flow during LR axis formation that has not been described in bpk and jcpk mice

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Left-right (LR) asymmetry of the visceral situs is established by Nodal signals from the posterior notochord (PNC), known as the ventral node in mammals (Brennan et al, 2002; Levin et al, 1995), Kupffer’s vesicle in zebrafish, or the gastrocoel roof plate (GRP) in Xenopus (Essner et al, 2002; Schweickert et al, 2007) These structures extrude motile cilia, which propel a leftward fluid flow to activate Nodal by an unknown mechanism on the left side (Nonaka et al, 2002; Nonaka et al, 1998) (reviewed by Shiratori and Hamada, 2006).

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