The role of compartmentalized signaling in primary cilia during tissue morphogenesis is not well understood. The cilia-localized G-protein-coupled receptor—Gpr161 represses hedgehog pathway via cAMP signaling. We engineered a knock-in at Gpr161 locus in mice to generate a variant (Gpr161mut1), which was ciliary localization defective but cAMP signaling competent. Tissue phenotypes from hedgehog signaling depend on downstream bifunctional Gli transcriptional factors functioning as activators/repressors. Compared to knockout (ko), Gpr161mut1/ko had delayed embryonic lethality, moderately increased hedgehog targets and partially down-regulated Gli3-repressor. Unlike ko, the Gpr161mut1/ko neural tube did not show Gli2-activator-dependent expansion of ventral-most progenitors. Instead, the intermediate neural tube showed progenitor expansion that depends on loss of Gli3-repressor. Increased extraciliary receptor (Gpr161mut1/mut1) prevented ventralization. Morphogenesis in limb buds and midface requires Gli-repressor; these tissues in Gpr161mut1/mut1 manifested hedgehog hyperactivation phenotypes—polydactyly and midfacial widening. Thus, ciliary and extraciliary Gpr161 pools likely establish tissue-specific Gli-repressor thresholds in determining morpho-phenotypic outcomes.
- Gli repressor
- Limb bud
- Neural tube
- Polydactyly, morphogenesis
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)