Protein kinase A (PKA), a conserved negative regulator of the hedgehog (Hh) signalling pathway, generates the transcriptional repressor form of Gli3 in the absence of Hh in mice. Now, Kathryn Anderson and colleagues show that the total loss of PKA activity in mouse embryos leads to a completely ventralised neural tube and mid-gestation lethality (see ), which indicates that the sonic hedgehog (Shh) signalling pathway is maximally activated in all neural progenitors in the absence of PKA. Notably, genetic experiments indicate that the principal function of PKA in the neural plate is to prevent Gli2 activation of Shh targets. Other experiments reveal that Hh pathway activation in PKA mutants depends on cilia, that PKA is localised at the basal body of primary cilia, and that Gli2 levels are increased at the tips of cilia of PKA-null cells. The researchers propose, therefore, that two separate cilia-associated compartments determine the accessibility of Gli proteins to PKA and thus the activity of the Shh pathway in vertebrates.
