Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 327 (5965): 547-552

Copyright © 2010 by the American Association for the Advancement of Science

Local and Long-Range Reciprocal Regulation of cAMP and cGMP in Axon/Dendrite Formation

Maya Shelly,1,* Byung Kook Lim,1,* Laura Cancedda,1,2 Sarah C. Heilshorn,1,{dagger} Hongfeng Gao,1 Mu-ming Poo1,{ddagger}

Abstract: Cytosolic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) often mediate antagonistic cellular actions of extracellular factors, from the regulation of ion channels to cell volume control and axon guidance. We found that localized cAMP and cGMP activities in undifferentiated neurites of cultured hippocampal neurons promote and suppress axon formation, respectively, and exert opposite effects on dendrite formation. Fluorescence resonance energy transfer imaging showed that alterations of the amount of cAMP resulted in opposite changes in the amount of cGMP, and vice versa, through the activation of specific phosphodiesterases and protein kinases. Local elevation of cAMP in one neurite resulted in cAMP reduction in all other neurites of the same neuron. Thus, local and long-range reciprocal regulation of cAMP and cGMP together ensures coordinated development of one axon and multiple dendrites.

1 Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA.
2 Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Via Morego 30, Genoa 16163, Italy.

* These authors contributed equally to this work.

{dagger}Present address: Department of Materials Science and Engineering, Geballe Laboratory for Advanced Materials, Stanford University, Stanford, CA 94305, USA.

{ddagger}To whom correspondence should be addressed. E-mail: mpoo{at}

Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology.
W. J. Buchser, T. I. Slepak, O. Gutierrez-Arenas, J. L. Bixby, and V. P. Lemmon (2014)
Mol Syst Biol 6, 391
   Abstract »    Full Text »    PDF »
EphA7 signaling guides cortical dendritic development and spine maturation.
M. A. Clifford, W. Athar, C. E. Leonard, A. Russo, P. J. Sampognaro, M.-S. Van der Goes, D. A. Burton, X. Zhao, R. R. Lalchandani, M. Sahin, et al. (2014)
PNAS 111, 4994-4999
   Abstract »    Full Text »    PDF »
Protein kinase LKB1 regulates polarized dendrite formation of adult hippocampal newborn neurons.
W. Huang, L. She, X.-y. Chang, R.-r. Yang, L. Wang, H.-b. Ji, J.-w. Jiao, and M.-m. Poo (2014)
PNAS 111, 469-474
   Abstract »    Full Text »    PDF »
Function of the Drosophila receptor guanylyl cyclase Gyc76C in PlexA-mediated motor axon guidance.
K. Chak and A. L. Kolodkin (2014)
Development 141, 136-147
   Abstract »    Full Text »    PDF »
Cell biology in neuroscience: Cellular and molecular mechanisms underlying axon formation, growth, and branching.
T. L. Lewis Jr., J. Courchet, and F. Polleux (2013)
J. Cell Biol. 202, 837-848
   Abstract »    Full Text »    PDF »
In vivo genetic dissection of O2-evoked cGMP dynamics in a Caenorhabditis elegans gas sensor.
A. Couto, S. Oda, V. O. Nikolaev, Z. Soltesz, and M. de Bono (2013)
PNAS 110, E3301-E3310
   Abstract »    Full Text »    PDF »
Striatal neurones have a specific ability to respond to phasic dopamine release.
L. R. V. Castro, M. Brito, E. Guiot, M. Polito, C. W. Korn, D. Herve, J.-A. Girault, D. Paupardin-Tritsch, and P. Vincent (2013)
J. Physiol. 591, 3197-3214
   Abstract »    Full Text »    PDF »
Nitric Oxide Synthesis and cGMP Production Is Important for Neurite Growth and Synapse Remodeling after Axotomy.
R. M. Cooke, R. Mistry, R. A. J. Challiss, and V. A. Straub (2013)
J. Neurosci. 33, 5626-5637
   Abstract »    Full Text »    PDF »
Activity-dependent competition regulates motor neuron axon pathfinding via PlexinA3.
P. V. Plazas, X. Nicol, and N. C. Spitzer (2013)
PNAS 110, 1524-1529
   Abstract »    Full Text »    PDF »
Cyclic AMP regulates formation of mammary epithelial acini in vitro.
P. I. Nedvetsky, S.-H. Kwon, J. Debnath, and K. E. Mostov (2012)
Mol. Biol. Cell 23, 2973-2981
   Abstract »    Full Text »    PDF »
Soluble Adenylyl Cyclase Activity Is Necessary for Retinal Ganglion Cell Survival and Axon Growth.
R. G. Corredor, E. F. Trakhtenberg, W. Pita-Thomas, X. Jin, Y. Hu, and J. L. Goldberg (2012)
J. Neurosci. 32, 7734-7744
   Abstract »    Full Text »    PDF »
Phosphorylation of Doublecortin by Protein Kinase A Orchestrates Microtubule and Actin Dynamics to Promote Neuronal Progenitor Cell Migration.
M. Toriyama, N. Mizuno, T. Fukami, T. Iguchi, M. Toriyama, K. Tago, and H. Itoh (2012)
J. Biol. Chem. 287, 12691-12702
   Abstract »    Full Text »    PDF »
Novel G{alpha}S-Protein Signaling Associated with Membrane-Tethered Amyloid Precursor Protein Intracellular Domain.
C. Deyts, K. S. Vetrivel, S. Das, Y. M. Shepherd, D. J. Dupre, G. Thinakaran, and A. T. Parent (2012)
J. Neurosci. 32, 1714-1729
   Abstract »    Full Text »    PDF »
Phosphorylation of CRMP2 (Collapsin Response Mediator Protein 2) Is Involved in Proper Dendritic Field Organization.
N. Yamashita, T. Ohshima, F. Nakamura, P. Kolattukudy, J. Honnorat, K. Mikoshiba, and Y. Goshima (2012)
J. Neurosci. 32, 1360-1365
   Abstract »    Full Text »    PDF »
Adenylate cyclase 5 coordinates the action of ADP, P2Y1, P2Y13 and ATP-gated P2X7 receptors on axonal elongation.
A. del Puerto, J.-I. Diaz-Hernandez, M. Tapia, R. Gomez-Villafuertes, M. J. Benitez, J. Zhang, M. T. Miras-Portugal, F. Wandosell, M. Diaz-Hernandez, and J. J. Garrido (2012)
J. Cell Sci. 125, 176-188
   Abstract »    Full Text »    PDF »
Type VI Adenylyl Cyclase Regulates Neurite Extension by Binding to Snapin and Snap25.
C.-S. Wu, J.-T. Lin, C.-L. Chien, W.-C. Chang, H.-L. Lai, C.-P. Chang, and Y. Chern (2011)
Mol. Cell. Biol. 31, 4874-4886
   Abstract »    Full Text »    PDF »
Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.
M. Kvajo, H. McKellar, L. J. Drew, A.-M. Lepagnol-Bestel, L. Xiao, R. J. Levy, R. Blazeski, P. A. Arguello, C. O. Lacefield, C. A. Mason, et al. (2011)
PNAS 108, E1349-E1358
   Abstract »    Full Text »    PDF »
Self-amplifying autocrine actions of BDNF in axon development.
P.-L. Cheng, A.-H. Song, Y.-H. Wong, S. Wang, X. Zhang, and M.-M. Poo (2011)
PNAS 108, 18430-18435
   Abstract »    Full Text »    PDF »
Spatiotemporally Regulated Protein Kinase A Activity Is a Critical Regulator of Growth Factor-Stimulated Extracellular Signal-Regulated Kinase Signaling in PC12 Cells.
K. J. Herbst, M. D. Allen, and J. Zhang (2011)
Mol. Cell. Biol. 31, 4063-4075
   Abstract »    Full Text »    PDF »
Spatial and temporal second messenger codes for growth cone turning.
X. Nicol, K. P. Hong, and N. C. Spitzer (2011)
PNAS 108, 13776-13781
   Abstract »    Full Text »    PDF »
Spatial Phosphoprotein Profiling Reveals a Compartmentalized Extracellular Signal-regulated Kinase Switch Governing Neurite Growth and Retraction.
Y. Wang, F. Yang, Y. Fu, X. Huang, W. Wang, X. Jiang, M. A. Gritsenko, R. Zhao, M. E. Monore, O. C. Pertz, et al. (2011)
J. Biol. Chem. 286, 18190-18201
   Abstract »    Full Text »    PDF »
Micropatterning as a tool to decipher cell morphogenesis and functions.
M. Thery (2010)
J. Cell Sci. 123, 4201-4213
   Abstract »    Full Text »    PDF »
Nitric Oxide Synthase Regulates Morphogenesis of Zebrafish Spinal Cord Motoneurons.
S. Bradley, K. Tossell, R. Lockley, and J. R. McDearmid (2010)
J. Neurosci. 30, 16818-16831
   Abstract »    Full Text »    PDF »
Competitive Outgrowth of Neural Processes Arising from Long-Distance cAMP Signaling.
B. I. Hutchins (2010)
Science Signaling 3, jc1
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882