Ciliary Adenylyl Cyclases control the Hedgehog pathway

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 (AC), the influence of these enzymes on the Hh pathway remains unclear. Here we show that AC5 and AC6 are the two isoforms most strongly expressed in cerebellar granular neuron precursors (CGNPs) and that that while over-expression of AC5 and AC6 represses the Hh pathway, their knockdown results in the activation of this pathway in CGNPs and in the embryonic neural tube (NT). 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, that are engaged by the G protein coupled receptors (GPCRs), control AC5 and AC6 activity and regulate Hh pathway in CGNPs and NT. Therefore, we propose that the activity of different ciliary GPCRs converge on AC5 and AC6 to control PKA activity and hence the Hh pathway.