The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling

Saikat Mukhopadhyay; Xiaohui Wen; Navneet Ratti; Alexander Loktev; Linda Rangell; Suzie J. Scales; Peter K. Jackson

doi:10.1016/j.cell.2012.12.026

The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling

Saikat Mukhopadhyay, Xiaohui Wen, Navneet Ratti, Alexander Loktev, Linda Rangell, Suzie J. Scales, Peter K. Jackson

Research output: Contribution to journal › Article

180 Citations (Scopus)

Abstract

The primary cilium is required for Sonic hedgehog (Shh) signaling in vertebrates. In contrast to mutants affecting ciliary assembly, mutations in the intraflagellar transport complex A (IFT-A) paradoxically cause increased Shh signaling. We previously showed that the IFT-A complex, in addition to its canonical role in retrograde IFT, binds to the tubby-like protein, Tulp3, and recruits it to cilia. Here, we describe a conserved vertebrate G-protein-coupled receptor, Gpr161, which localizes to primary cilia in a Tulp3/IFT-A-dependent manner. Complete loss of Gpr161 in mouse causes midgestation lethality and increased Shh signaling in the neural tube, phenocopying Tulp3/IFT-A mutants. Constitutive Gpr161 activity increases cAMP levels and represses Shh signaling by determining the processing of Gli3 to its repressor form. Conversely, Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity. Thus, Gpr161 defines a morphogenetic pathway coupling protein kinase A activation to Shh signaling during neural tube development.

Original language	English (US)
Pages (from-to)	210-223
Number of pages	14
Journal	Cell
Volume	152
Issue number	1-2
DOIs	https://doi.org/10.1016/j.cell.2012.12.026
State	Published - Jan 7 2013

Fingerprint

Hedgehogs

G-Protein-Coupled Receptors

Cilia

Neural Tube

Vertebrates

Cyclic AMP-Dependent Protein Kinases

Chemical activation

Mutation

Processing

Proteins

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mukhopadhyay, S., Wen, X., Ratti, N., Loktev, A., Rangell, L., Scales, S. J., & Jackson, P. K. (2013). The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling. Cell, 152(1-2), 210-223. https://doi.org/10.1016/j.cell.2012.12.026

The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling. / Mukhopadhyay, Saikat; Wen, Xiaohui; Ratti, Navneet; Loktev, Alexander; Rangell, Linda; Scales, Suzie J.; Jackson, Peter K.

In: Cell, Vol. 152, No. 1-2, 07.01.2013, p. 210-223.

Research output: Contribution to journal › Article

Mukhopadhyay, S, Wen, X, Ratti, N, Loktev, A, Rangell, L, Scales, SJ & Jackson, PK 2013, 'The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling', Cell, vol. 152, no. 1-2, pp. 210-223. https://doi.org/10.1016/j.cell.2012.12.026

Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ et al. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling. Cell. 2013 Jan 7;152(1-2):210-223. https://doi.org/10.1016/j.cell.2012.12.026

Mukhopadhyay, Saikat ; Wen, Xiaohui ; Ratti, Navneet ; Loktev, Alexander ; Rangell, Linda ; Scales, Suzie J. ; Jackson, Peter K. / The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling. In: Cell. 2013 ; Vol. 152, No. 1-2. pp. 210-223.

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10.1016/j.cell.2012.12.026