Research ArticleDevelopmental Biology

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

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Science Signaling  06 Feb 2018:
Vol. 11, Issue 516, eaao5749
DOI: 10.1126/scisignal.aao5749

GPCRs reduce sensitivity to Sonic Hedgehog

In the developing spinal cord, Sonic Hedgehog (SHH) released from the notochord and floor plate induces overlying neural progenitor cells (NPCs) to differentiate into different neural cell types in a concentration-dependent manner. Pusapati et al. found that loss of the G protein–coupled receptor (GPCR) GPR161 sensitized both cultured fibroblasts and NPCs to SHH. The ability of Gαs, which is activated by GPR161, to negatively regulate SHH signaling did not strictly depend on GPR161, suggesting that other GPCRs that couple to Gαs may also attenuate SHH signaling. Although GPCR kinase 2 (GRK2) is proposed to promote SHH signaling by removing GPR161 from the primary cilium, the authors found that GRK2 enhanced SHH signaling independently of GPR161. GRK2, GPR161, and Gαs tuned cellular sensitivity to SHH likely by affecting the extent of protein kinase A activity, a negative regulator of SHH signaling (see also Focus by Sharpe and de Sauvage).


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.

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