cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A.
cAMP is a key mediator of a number of molecules that induce growth cone chemotaxis, including netrin-1 and myelin-associated glycoprotein (MAG). Endogenous neuronal cAMP levels decline during development, and concomitantly axonal growth cones switch their response to cAMP-dependent guidance cues from attraction to repulsion. The mechanisms by which cAMP regulates these polarized growth cone responses are unknown. We report that embryonic growth cone attraction to gradients of cAMP, netrin-1, or MAG is mediated by Epac. Conversely, the repulsion conferred by MAG or netrin-1 on adult growth cones is mediated by protein kinase A (PKA). Furthermore, fluorescence resonance energy transfer reveals that netrin-1 distinctly activates Epac in embryonic growth cones but PKA in postnatal neurons. Our results suggest that cAMP mediates growth cone attraction or repulsion by distinctly activating Epac or PKA, respectively. Moreover, we propose that the developmental switch in growth cone response to gradients of cAMP-dependent guidance cues from attraction to repulsion is the result of a switch from Epac- to PKA-mediated signaling pathways.
Murray
Andrew J
AJ
Institute of Medical Sciences, School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Forresterhill, Aberdeen AB25 2ZD, United Kingdom. a.j.murray@abdn.ac.uk
Tucker
Steven J
SJ
Shewan
Derryck A
DA
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D005727:Ganglia, Spinal / Q000196:embryology / Q000254:growth & development* / Q000502:physiology*; D020439:Growth Cones / Q000502:physiology*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D000075388:Netrin-1; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018992:Myelin-Associated Glycoprotein; D009414:Nerve Growth Factors; C000617354:Ntn1 protein, rat; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D000242:Cyclic AMP; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D002118:Calcium