Ciliary and extraciliary gpr161 pools repress hedgehog signaling in a tissue-specific manner

Sun Hee Hwang, Bandarigoda N. Somatilaka, Kevin White, Saikat Mukhopadhyay

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournaleLife
Volume10
DOIs
StatePublished - 2021

Keywords

  • CAMP
  • Cilia
  • Craniofacial
  • Gli repressor
  • Gpr161
  • Hedgehog
  • Limb bud
  • Neural tube
  • Polydactyly, morphogenesis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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