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.
Subscribe

Sci. Signal., 6 December 2011
Vol. 4, Issue 202, p. ra82
[DOI: 10.1126/scisignal.2002060]

RESEARCH ARTICLES

Neuronal Growth Cone Retraction Relies on Proneurotrophin Receptor Signaling Through Rac

Katrin Deinhardt1, Taeho Kim2*, Daniel S. Spellman3, Richard E. Mains4, Betty A. Eipper4, Thomas A. Neubert3, Moses V. Chao1, and Barbara L. Hempstead2{dagger}

1 Departments of Cell Biology, Physiology and Neuroscience, and Psychiatry and Center for Neural Science, Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
2 Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
3 Department of Pharmacology and Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
4 Neuroscience Department, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.

* Present address: Bio-X and Department of Biology, Stanford University, Stanford, CA 94305, USA.

Abstract: Growth of axons and dendrites is a dynamic process that involves guidance molecules, adhesion proteins, and neurotrophic factors. Although neurite extension is stimulated by the neurotrophin nerve growth factor (NGF), we found that the precursor of NGF, proNGF, induced acute collapse of growth cones of cultured hippocampal neurons. This retraction was initiated by an interaction between the p75 neurotrophin receptor (p75NTR) and the sortilin family member SorCS2 (sortilin-related VPS10 domain–containing receptor 2). Binding of proNGF to the p75NTR-SorCS2 complex induced growth cone retraction by initiating the dissociation of the guanine nucleotide exchange factor Trio from the p75NTR-SorCS2 complex, resulting in decreased Rac activity and, consequently, growth cone collapse. The actin-bundling protein fascin was also inactivated, contributing to the destabilization and collapse of actin filaments. These results identify a bifunctional signaling mechanism by which proNGF regulates actin dynamics to acutely modulate neuronal morphology.

{dagger} To whom correspondence should be addressed. E-mail: blhempst{at}med.cornell.edu

Citation: K. Deinhardt, T. Kim, D. S. Spellman, R. E. Mains, B. A. Eipper, T. A. Neubert, M. V. Chao, B. L. Hempstead, Neuronal Growth Cone Retraction Relies on Proneurotrophin Receptor Signaling Through Rac. Sci. Signal. 4, ra82 (2011).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
ProNGF promotes neurite growth from a subset of NGF-dependent neurons by a p75NTR-dependent mechanism.
L. Howard, S. Wyatt, G. Nagappan, and A. M. Davies (2013)
Development 140, 2108-2117
   Abstract »    Full Text »    PDF »
Of Proneurotrophins and Their Antineurotrophic Effects.
L. Kotlyanskaya, K. A. McLinden, and E. Giniger (2013)
Science Signaling 6, pe6
   Abstract »    Full Text »    PDF »
A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions.
R. Kraft, A. Kahn, J. L. Medina-Franco, M. L. Orlowski, C. Baynes, F. Lopez-Vallejo, K. Barnard, G. M. Maggiora, and L. L. Restifo (2013)
Dis. Model. Mech. 6, 217-235
   Abstract »    Full Text »    PDF »
The E3 ligase APC/C-Cdh1 is required for associative fear memory and long-term potentiation in the amygdala of adult mice.
J. E. Pick, M. Malumbres, and E. Klann (2012)
Learn. Mem. 20, 11-20
   Abstract »    Full Text »    PDF »
ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation.
C.-J. Siao, C. U. Lorentz, P. Kermani, T. Marinic, J. Carter, K. McGrath, V. A. Padow, W. Mark, D. J. Falcone, L. Cohen-Gould, et al. (2012)
J. Exp. Med. 209, 2291-2305
   Abstract »    Full Text »    PDF »
Vps10 Family Proteins and the Retromer Complex in Aging-Related Neurodegeneration and Diabetes.
R. F. Lane, P. St George-Hyslop, B. L. Hempstead, S. A. Small, S. M. Strittmatter, and S. Gandy (2012)
J. Neurosci. 32, 14080-14086
   Abstract »    Full Text »    PDF »
Dependence of Regenerated Sensory Axons on Continuous Neurotrophin-3 Delivery.
S. Hou, L. Nicholson, E. van Niekerk, M. Motsch, and A. Blesch (2012)
J. Neurosci. 32, 13206-13220
   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