Ciliary adenylyl cyclases control the Hedgehog pathway

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adenylyl Cyclases / genetics*
  • Adenylyl Cyclases / metabolism
  • Animals
  • Cell Line
  • Cell Proliferation / genetics
  • Chick Embryo
  • Cilia / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • GTP-Binding Protein alpha Subunits / genetics
  • HEK293 Cells
  • Hedgehog Proteins / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / metabolism
  • Neural Tube / cytology
  • Neural Tube / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction / physiology
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3


  • GTP-Binding Protein alpha Subunits
  • Gli2 protein, mouse
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Shh protein, mouse
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3
  • Cyclic AMP-Dependent Protein Kinases
  • Adenylyl Cyclases
  • adenylyl cyclase 6
  • adenylyl cyclase type V