G protein-coupled receptor 161 (GPR161) is a key negative regulator of Shh signaling, which promotes the processing of GLI3 into GLI3R during neural tube development. Recruited by TULP3 and the IFT-A complex to primary cilia and acts as a regulator of the PKA-dependent basal repression machinery in Shh signaling by increasing cAMP levels, leading to promote the PKA-dependent processing of GLI3 into GLI3R and repress the Shh signaling. GPR161, in presence of SHH, is removed from primary cilia and is internalized into recycling endosomes, preventing its activity and allowing activation of the Shh signaling. It has also been reported to regulate forelimb formation and skeletal morphogenesis. References: Development 2018 145: dev154054 doi: 10.1242/dev.154054 Published 8 January 2018