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 journalArticle

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 languageEnglish (US)
Pages (from-to)210-223
Number of pages14
JournalCell
Volume152
Issue number1-2
DOIs
StatePublished - Jan 7 2013

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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

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 journalArticle

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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