Signaling to transcription networks in the neuronal retrograde injury response.
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 approximately 900 phosphoproteins in retrograde injury signaling in rat sciatic nerve axons in vivo and approximately 4500 transcripts in the in vivo response to injury in the dorsal root ganglia. Computational analyses of these data sets identified approximately 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.
Michaelevski
Izhak
I
Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
Segal-Ruder
Yael
Y
Rozenbaum
Meir
M
Medzihradszky
Katalin F
KF
Shalem
Ophir
O
Coppola
Giovanni
G
Horn-Saban
Shirley
S
Ben-Yaakov
Keren
K
Dagan
Shachar Y
SY
Rishal
Ida
I
Geschwind
Daniel H
DH
Pilpel
Yitzhak
Y
Burlingame
Alma L
AL
Fainzilber
Mike
M
D000818:Animals; D005727:Ganglia, Spinal / Q000293:injuries; D053263:Gene Regulatory Networks / Q000502:physiology*; D009416:Nerve Regeneration; D016501:Neurites; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D059348:Peripheral Nerve Injuries; D010750:Phosphoproteins / Q000032:analysis; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012183:Retrograde Degeneration; D012584:Sciatic Nerve / Q000293:injuries; D015398:Signal Transduction / Q000502:physiology*
D010750:Phosphoproteins; D012333:RNA, Messenger