Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

The role of compartmentalized cAMP signaling in primary cilia is not well understood. The cilia-localized G-protein-coupled receptor—Gpr161 represses hedgehog pathway via cAMP signaling. Here, by generating knock-in mutant mouse at endogenous Gpr161 locus ( mut1 ), we show that ciliary and extraciliary receptor pools repress hedgehog signaling in a tissue-specific manner. Gpr161 mut1 was competent in generating cAMP but did not transit through cilia. Compared to knockout, Gpr161 mut1 had delayed embryonic lethality, less upregulation of hedgehog targets and partially down-regulated Gli3-repressor. Ventral-most progenitor expansion in neural tube of Gpr161 knockout occurred in a Gli2-activator-dependent manner but was not seen in Gpr161 mut1 . Intermediate-level ventralization occurred from Gpr161 lack specifically in cilia but was restored by increased extraciliary mutant generating Gli3-repressor. Morphogenesis in limb buds and midface that require Gli-repressor manifested hedgehog hyperactivation phenotypes— polydactyly and midfacial widening—in Gpr161 mut1 . Thus, ciliary and extraciliary cAMP signaling establishes tissue-specific Gli-repressor thresholds in dictating morpho-phenotypic outcomes. Impact statement Signaling by Cilia Signaling by cAMP specifically in cilia directs tissue-specific morphogenesis