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Ciliary adenylyl cyclases control the Hedgehog pathway

AuthorsVuolo, Laura CSIC; Herrera, Antonio CSIC ORCID ; Torroba, Blanca; Menendez, Anghara CSIC ; Pons, Sebastián CSIC ORCID
KeywordsAdenylyl cyclase
Cerebellar granular neuron precursor
Hedgehog pathway
Primary cilium
Issue Date15-Jun-2015
PublisherCompany of Biologists
CitationJournal of Cell Science 128: 2928-2937 (2015)
AbstractProtein 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
Publisher version (URL)http://dx.doi.org/10.1242/jcs.172635
Identifiersdoi: 10.1242/jcs.172635
issn: 0021-9533
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