ABSTRACT
Protein kinase A (PKA) accumulates at the base of the cilium where it negatively regulates the Hedgehog (Hh) pathway. Although PKA activity is essentially controlled by the cAMP produced by adenylyl cyclases, the influence of these enzymes on the Hh pathway remains unclear. Here, we show that adenylyl cyclase 5 and adenylyl cyclase 6 (AC5 and AC6, also known as ADCY5 and ADCY6, respectively) are the two isoforms most strongly expressed in cerebellar granular neuron precursors (CGNPs). We found that overexpression of AC5 and AC6 represses, whereas their knockdown activates, the Hh pathway in CGNPs and in the embryonic neural tube. Indeed, AC5 and AC6 concentrate in the primary cilium, and mutation of a previously undescribed cilium-targeting motif in AC5 suppresses its ciliary location, as well as its capacity to inhibit Hh signalling. Stimulatory and inhibitory Gα proteins, which are engaged by the G-protein-coupled receptors (GPCRs), control AC5 and AC6 activity and regulate the Hh pathway in CGNPs and in the neural tube. Therefore, we propose that the activity of different ciliary GPCRs converges on AC5 and AC6 to control PKA activity and, hence, the Hh pathway.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
S.P. conceived the study, L.V. designed performed and analysed most of the experiments, A.H. did neural tube patterning experiments; B.T. performed BrdU incorporation and short hairpin cloning duties. A.M. provided technical assistance, S.P. wrote the paper.
Funding
This work was supported by Spanish and Catalan ministries of Science [grant numbers BFU2008-02424/BFI, BFU2011-24099 and SGR200821A333 to S.P.]
Supplementary material
Supplementary material available online at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.172635/-/DC1
- Received April 2, 2015.
- Accepted June 15, 2015.
- © 2015. Published by The Company of Biologists Ltd
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