Soluble Adenylyl Cyclase Is Not Required for Axon Guidance to Netrin-1

Abstract

During development, axons are directed to their targets by extracellular guidance cues. The axonal response to the guidance cue netrin-1 is profoundly influenced by the concentration of cAMP within the growth cone. In some cases, cAMP affects the sensitivity of the growth cone to netrin-1, whereas in others it changes the response to netrin-1 from attraction to repulsion. The effects of cAMP on netrin-1 action are well accepted, but the critical issue of whether cAMP production is activated by a netrin-1 induced signaling cascade remains uncertain. A previous report has suggested that axon guidance in response to netrin-1 requires cAMP production mediated by soluble adenyl cyclase (sAC). We have used genetic, molecular and biochemical strategies to assess this issue. Surprisingly, we found only extremely weak expression of sAC in embryonic neurons and determined that, under conditions where netrin-1 directs axonal pathfinding, exposure to netrin-1 does not alter cAMP levels. Furthermore, although netrin-1-deficient mice exhibit major axon guidance defects, we show that pathfinding is normal in sAC-null mice. Therefore, although cAMP can alter the response of axons to netrin-1, we conclude that netrin-1 does not alter cAMP levels in axons attracted by this cue, and that sAC is not required for axon attraction to netrin-1.

Spatial and temporal second messenger codes for growth cone turning

“…has been contentious. In vitro, cAMP induces a switch in the response to Netrin-1 (8), but genetic deletion of soluble adenylyl cyclase fails to produce a defect in guidance of spinal commissural neurons in mice (32). We imaged growth of Xenopus laevis spinal commissural axons to determine whether cAMP signaling regulates axon guidance in vivo (Fig.…”

Netrin-1 Regulates Th1/Th2/Th17 Cytokine Production and Inflammation through UNC5B Receptor and Protects Kidney against Ischemia–Reperfusion Injury

“…However, the signaling pathway through which netrin-1 suppresses cytokine production is not clear. Netrin-1 is known to activate adenylate cyclase/cAMP pathways (43,44). cAMP/protein kinase A-mediated activation of CREB protein suppresses cytokine production from immune cells (45,46).…”

Ena/VASP: proteins at the tip of the nervous system

“…It is important to note, however, that while PKA activity can regulate the sensitivity of axons to Netrin-1, a direct role for PKA in guidance conversion has not been observed [61]. In addition, Netrin-1 stimulation does not activate PKA [62]. It seems likely that PKA phosphorylation of Ena/VASP may be triggered by other cues, for example changes in the extracellular matrix [63].…”