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Sci. Signal., 13 July 2010
Vol. 3, Issue 130, p. ra53
[DOI: 10.1126/scisignal.2000952]

RESEARCH ARTICLES

Signaling to Transcription Networks in the Neuronal Retrograde Injury Response

Izhak Michaelevski1*, Yael Segal-Ruder1*, Meir Rozenbaum1, Katalin F. Medzihradszky2, Ophir Shalem3, Giovanni Coppola4, Shirley Horn-Saban5, Keren Ben-Yaakov1, Shachar Y. Dagan1, Ida Rishal1, Daniel H. Geschwind4, Yitzhak Pilpel3, Alma L. Burlingame2, and Mike Fainzilber1{dagger}

1 Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
2 Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94158-2517, USA.
3 Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel.
4 Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
5 Department of Biological Services, Weizmann Institute of Science, 76100 Rehovot, Israel.

* These authors contributed equally to this work.

Abstract: Retrograde signaling from axon to soma activates intrinsic regeneration mechanisms in lesioned peripheral sensory neurons; however, the links between axonal injury signaling and the cell body response are not well understood. Here, we used phosphoproteomics and microarrays to implicate ~900 phosphoproteins in retrograde injury signaling in rat sciatic nerve axons in vivo and ~4500 transcripts in the in vivo response to injury in the dorsal root ganglia. Computational analyses of these data sets identified ~400 redundant axonal signaling networks connected to 39 transcription factors implicated in the sensory neuron response to axonal injury. Experimental perturbation of individual overrepresented signaling hub proteins, including Abl, AKT, p38, and protein kinase C, affected neurite outgrowth in sensory neurons. Paradoxically, however, combined perturbation of Abl together with other hub proteins had a reduced effect relative to perturbation of individual proteins. Our data indicate that nerve injury responses are controlled by multiple regulatory components, and suggest that network redundancies provide robustness to the injury response.

{dagger} To whom correspondence should be addressed. E-mail: mike.fainzilber{at}weizmann.ac.il

Citation: I. Michaelevski, Y. Segal-Ruder, M. Rozenbaum, K. F. Medzihradszky, O. Shalem, G. Coppola, S. Horn-Saban, K. Ben-Yaakov, S. Y. Dagan, I. Rishal, D. H. Geschwind, Y. Pilpel, A. L. Burlingame, M. Fainzilber, Signaling to Transcription Networks in the Neuronal Retrograde Injury Response. Sci. Signal. 3, ra53 (2010).

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