RT Journal Article
SR Electronic
T1 Ciliary adenylyl cyclases control the Hedgehog pathway
JF Journal of Cell Science
JO J. Cell Sci.
FD The Company of Biologists Ltd
SP 2928
OP 2937
DO 10.1242/jcs.172635
VO 128
IS 15
A1 Vuolo, Laura
A1 Herrera, Antonio
A1 Torroba, Blanca
A1 Menendez, Anghara
A1 Pons, Sebastian
YR 2015
UL http://jcs.biologists.org/content/128/15/2928.abstract
AB 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.