Routes to cAMP: shaping neuronal connectivity with distinct adenylate cyclases

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cAMP signaling affects a large number of the developmental processes needed for the construction of the CNS, including cell differentiation, axon outgrowth, response to guidance molecules or modulation of synaptic connections. This points to a key role of adenylate cyclases (ACs), the synthetic enzymes of cAMP, for neural development. ACs exist as 10 different isoforms, which are activated by distinct signaling pathways. The implication of specific AC isoforms in neural wiring was only recently demonstrated in mouse mutants, knockout (KO) for different AC isoforms, AC1, AC3, AC5, AC8 and soluble (s)AC/AC10. These studies stressed the importance of three of these isoforms, as sensors of neural activity that could modify the survival of neurons (sAC), axon outgrowth (sAC), or the response of axons to guidance molecules such as ephrins (AC1) or semaphorins (AC3). We summarize here the current knowledge on the role of these ACs for the development of sensory maps, in the somatosensory, visual and olfactory systems, which have been the most extensively studied. In these systems, AC1/AC3 KO revealed targeting mistakes due to the defective pruning and lack of discrimination of incoming axons to signals present in target structures. In contrast, no changes in cell differentiation, survival or axon outgrowth were noted in these mutants, suggesting a specificity of cAMP production routes for individual cellular processes within a given neuron. Further studies indicate that the subcellular localization of ACs could be key to their specific role in axon targeting and may explain their selective roles in neuronal wiring.

How cAMP signals are precisely controlled in time and space to produce such a broad range of developmental effects remains unknown, but one of the key elements in this process lies in the regulation of the enzymes that produce cAMP, the adenylate cyclases (ACs). AC mutants that are defective for a subset of the calcium sensitive isoforms, namely AC1, AC3 and AC10, have defects in neural wiring in main developmental model systems such as the barrel cortex, the visual pathways, the olfactory system, and the corticospinal tract. Studies over the last ten years emphasized the role of calcium-stimulated adenylate cyclases during late stages of neural circuit wiring suggesting that a main function of these ACs during development would be to act as integrators of neural activity and axon guidance molecules.

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