G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog

Ganesh V Pusapati, Jennifer H Kong, Bhaven B Patel, Mina Gouti, Andreas Sagner, Ria Sircar, Giovanni Luchetti, Philip W Ingham, James Briscoe, Rajat Rohatgi

Research output: Contribution to journalArticlepeer-review

45 Citations (SciVal)


The morphogen Sonic Hedgehog (SHH) patterns tissues during development by directing cell fates in a concentration-dependent manner. The SHH signal is transmitted across the membrane of target cells by the heptahelical transmembrane protein Smoothened (SMO), which activates the GLI family of transcription factors through a mechanism that is undefined in vertebrates. Using CRISPR-edited null alleles and small-molecule inhibitors, we systematically analyzed the epistatic interactions between SMO and three proteins implicated in SMO signaling: the heterotrimeric G protein subunit GαS, the G protein-coupled receptor kinase 2 (GRK2), and the GαS-coupled receptor GPR161. Our experiments uncovered a signaling mechanism that modifies the sensitivity of target cells to SHH and consequently changes the shape of the SHH dose-response curve. In both fibroblasts and spinal neural progenitors, the loss of GPR161, previously implicated as an inhibitor of basal SHH signaling, increased the sensitivity of target cells across the entire spectrum of SHH concentrations. Even in cells lacking GPR161, GRK2 was required for SHH signaling, and Gαs, which promotes the activation of protein Kinase A (PKA), antagonized SHH signaling. We propose that the sensitivity of target cells to Hedgehog morphogens, and the consequent effects on gene expression and differentiation outcomes, can be controlled by signals from G protein-coupled receptors that converge on Gαs and PKA.

Original languageEnglish
Article numbereaao5749
Number of pages15
JournalScience Signaling
Issue number516
Publication statusPublished - 6 Feb 2018

Bibliographical note

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.


  • Animals
  • Cells, Cultured
  • Chromogranins/genetics
  • Cyclic AMP-Dependent Protein Kinases/genetics
  • Epistasis, Genetic
  • G-Protein-Coupled Receptor Kinase 2/genetics
  • GTP-Binding Protein alpha Subunits, Gs/genetics
  • HEK293 Cells
  • Hedgehog Proteins/genetics
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Receptors, G-Protein-Coupled/genetics
  • Signal Transduction
  • Smoothened Receptor/genetics


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