title: 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, 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.
authors.affiliation: Instituto de Biología Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Vuolo
authors.affiliation: Instituto de Biología Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Herrera
authors.affiliation: Instituto de Biología Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Torroba
authors.affiliation: Instituto de Biología Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain.
authors.forename: Anghara
authors.initials: A
authors.lastname: Menendez
authors.affiliation: Instituto de Biología Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain spfbmc@ibmb.csic.es.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pons
mesh_terms: D016475:3T3 Cells; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D002642:Chick Embryo; D002923:Cilia / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism; D054259:Neural Tube / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: D044385:GTP-Binding Protein alpha Subunits; C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C465570:Shh protein, mouse; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V
keywords: Adenylyl cyclase; Cerebellar granular neuron precursor; Hedgehog pathway; Primary cilium