TY - JOUR
T1 - The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling
AU - Mukhopadhyay, Saikat
AU - Wen, Xiaohui
AU - Ratti, Navneet
AU - Loktev, Alexander
AU - Rangell, Linda
AU - Scales, Suzie J.
AU - Jackson, Peter K.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2013/1/17
Y1 - 2013/1/17
N2 - The primary cilium is required for Sonic hedgehog (Shh) signaling in vertebrates. In contrast to mutants affecting ciliary assembly, mutations in the intraflagellar transport complex A (IFT-A) paradoxically cause increased Shh signaling. We previously showed that the IFT-A complex, in addition to its canonical role in retrograde IFT, binds to the tubby-like protein, Tulp3, and recruits it to cilia. Here, we describe a conserved vertebrate G-protein-coupled receptor, Gpr161, which localizes to primary cilia in a Tulp3/IFT-A-dependent manner. Complete loss of Gpr161 in mouse causes midgestation lethality and increased Shh signaling in the neural tube, phenocopying Tulp3/IFT-A mutants. Constitutive Gpr161 activity increases cAMP levels and represses Shh signaling by determining the processing of Gli3 to its repressor form. Conversely, Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity. Thus, Gpr161 defines a morphogenetic pathway coupling protein kinase A activation to Shh signaling during neural tube development.
AB - The primary cilium is required for Sonic hedgehog (Shh) signaling in vertebrates. In contrast to mutants affecting ciliary assembly, mutations in the intraflagellar transport complex A (IFT-A) paradoxically cause increased Shh signaling. We previously showed that the IFT-A complex, in addition to its canonical role in retrograde IFT, binds to the tubby-like protein, Tulp3, and recruits it to cilia. Here, we describe a conserved vertebrate G-protein-coupled receptor, Gpr161, which localizes to primary cilia in a Tulp3/IFT-A-dependent manner. Complete loss of Gpr161 in mouse causes midgestation lethality and increased Shh signaling in the neural tube, phenocopying Tulp3/IFT-A mutants. Constitutive Gpr161 activity increases cAMP levels and represses Shh signaling by determining the processing of Gli3 to its repressor form. Conversely, Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity. Thus, Gpr161 defines a morphogenetic pathway coupling protein kinase A activation to Shh signaling during neural tube development.
UR - http://www.scopus.com/inward/record.url?scp=84872508509&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872508509&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.12.026
DO - 10.1016/j.cell.2012.12.026
M3 - Article
C2 - 23332756
AN - SCOPUS:84872508509
VL - 152
SP - 210
EP - 223
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1-2
ER -