Calcium and cAMP levels interact to determine attraction versus repulsion in axon guidance

Correct guidance of axons to their targets depends on an intricate network of signaling molecules in the growth cone. Calcium and cAMP are two key regulators of whether axons are attracted or repelled by molecular gradients, but how these molecules interact to determine guidance responses remains unclear. Here, we constructed a mathematical model for the relevant signaling network, which explained a large range of previous biological data and made predictions for when axons will be attracted or repelled. We then confirmed these predictions experimentally, in particular showing that while small increases in cAMP levels promote attraction large increases do not, and that under some circumstances reducing cAMP levels promotes attraction. Together, these results show that a relatively simple mathematical model can quantitatively predict guidance decisions across a wide range of conditions, and that calcium and cAMP levels play a more complex role in these decisions than previously determined.