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.
Department of Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States.
Yan
Y
Hao
Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States.
Erin
E
Frey
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States.
Choya
C
Yoon
Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Hetty
H
Wong
Department of Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States.
Douglas
D
Nestorovski
Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Lawrence B
LB
Holzman
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States.|Department of Neurology, University of Michigan School of Medicine, Ann Arbor, United States.
Roman J
0000-0002-2926-3336
RJ
Giger
Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States.
Aaron
A
DiAntonio
Department of Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States.
Catherine
0000-0002-1608-6692
C
Collins
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004330:Drosophila / Q000201:enzymology* / Q000502:physiology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D009416:Nerve Regeneration
D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12
D. melanogaster; MAP Kinasae signaling; axonal regeneration; cAMP signaiing; mouse; neuroscience