An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK

A broadly known method to stimulate the growth potential of axons is to elevate intracellular levels of cAMP, however the cellular pathway(s) that mediate this are not known. Here we identify the Dual Leucine-zipper Kinase (DLK, Wnd in Drosophila) as a critical target and effector of cAMP in injured axons. DLK/Wnd is thought to function as an injury ‘sensor’, as it becomes activated after axonal damage. Our findings in both Drosophila and mammalian neurons indicate that the cAMP effector kinase PKA is a conserved and direct upstream activator of Wnd/DLK. PKA is required for the induction of Wnd signaling in injured axons, and DLK is essential for the regenerative effects of cAMP in mammalian DRG neurons. These findings link two important mediators of responses to axonal injury, DLK/Wnd and cAMP/PKA, into a unified and evolutionarily conserved molecular pathway for stimulating the regenerative potential of injured axons. DOI: http://dx.doi.org/10.7554/eLife.14048.001

eLife digest Adult mammals typically cannot repair damage to the nerve fibers in their brain or spinal cord. This is because these nerve cells cannot generally grow new nerve fibers. However this inability to regenerate nerve fibers is not set in stone. Instead, it can be unlocked by a second injury in nerves elsewhere in the body, the so-called “peripheral nervous system”. This process relies on an enzyme called DLK, which becomes activated in damaged nerve fibers. But how does DLK ‘sense’ damage to nerve fibers? Injuring the peripheral nervous system causes the levels of a molecule called cAMP to increase in the damaged nerve cells, and the elevated cAMP levels stimulate the nerve fibers to regenerate. However, it was not known if cAMP activates DLK, or if the two act independently of each other. By looking at the regeneration of damaged nerve fibers in fruit fly larvae, Hao et al. now show that the cAMP and DLK signaling pathways are clearly linked. Further experiments with nerve cells from mice and human cells revealed more detail about this link. Together the results showed that another enzyme called PKA activates DLK directly when cAMP levels are high. These findings reveal a unified pathway that is the key to unlocking the regenerative potential of injured nerve fibers, which has been conserved for hundreds of millions of years of evolution. Further work could now ask if the DLK enzyme is involved in the other known roles of cAMP signaling in nerve cells; or if cAMP and PKA activate DLK in other forms of nerve damage, including injuries where nerve fibers normally fail to regenerate. DOI: http://dx.doi.org/10.7554/eLife.14048.002