Format

Send to

Choose Destination
J Cell Sci. 2015 Aug 1;128(15):2928-37. doi: 10.1242/jcs.172635. Epub 2015 Jun 19.

Ciliary adenylyl cyclases control the Hedgehog pathway.

Author information

1
Instituto de Biología Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain.
2
Instituto de Biología Molecular de Barcelona (CSIC), Parc Científic de Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain spfbmc@ibmb.csic.es.

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.

KEYWORDS:

Adenylyl cyclase; Cerebellar granular neuron precursor; Hedgehog pathway; Primary cilium

PMID:
26092933
DOI:
10.1242/jcs.172635
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center