PMID- 19188931
OWN - NLM
STAT- MEDLINE
DCOM- 20090624
LR  - 20220321
IS  - 1748-7838 (Electronic)
IS  - 1001-0602 (Linking)
VI  - 19
IP  - 5
DP  - 2009 May
TI  - A retrograde apoptotic signal originating in NGF-deprived distal axons of rat 
      sympathetic neurons in compartmented cultures.
PG  - 546-60
LID - 10.1038/cr.2009.11 [doi]
AB  - Previous investigations of retrograde survival signaling by nerve growth factor 
      (NGF) and other neurotrophins have supported diverse mechanisms, but all proposed 
      mechanisms have in common the generation of survival signals retrogradely 
      transmitted to the neuronal cell bodies. We report the finding of a retrograde 
      apoptotic signal in axons that is suppressed by local NGF signaling. NGF 
      withdrawal from distal axons alone was sufficient to activate the pro-apoptotic 
      transcription factor, c-jun, in the cell bodies. Providing NGF directly to cell 
      bodies, thereby restoring a source of NGF-induced survival signals, could not 
      prevent c-jun activation caused by NGF withdrawal from the distal axons. This is 
      evidence that c-jun is not activated due to loss of survival signals at the cell 
      bodies. Moreover, blocking axonal transport with colchicine inhibited c-jun 
      activation caused by NGF deprivation suggesting that a retrogradely transported 
      pro-apoptotic signal, rather than loss of a retrogradely transported survival 
      signal, caused c-jun activation. Additional experiments showed that activation of 
      c-jun, pro-caspase-3 cleavage, and apoptosis were blocked by the protein kinase C 
      inhibitors, rottlerin and chelerythrine, only when applied to distal axons 
      suggesting that they block the axon-specific pro-apoptotic signal. The 
      rottlerin-sensitive mechanism was found to regulate glycogen synthase kinase 3 
      (GSK3) activity. The effect of siRNA knockdown, and pharmacological inhibition of 
      GSK3 suggests that GSK3 is required for apoptosis caused by NGF deprivation and 
      may function as a retrograde carrier of the axon apoptotic signal. The existence 
      of a retrograde death signaling system in axons that is suppressed by 
      neurotrophins has broad implications for neurodevelopment and for discovering 
      treatments for neurodegenerative diseases and neurotrauma.
FAU - Mok, Sue-Ann
AU  - Mok SA
AD  - Department of Cell Biology, University of Alberta, 5-14 Medical Sciences 
      Building, Edmonton, Alberta, Canada T6G 2H7.
FAU - Lund, Karen
AU  - Lund K
FAU - Campenot, Robert B
AU  - Campenot RB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Cell Res
JT  - Cell research
JID - 9425763
RN  - 0 (Acetophenones)
RN  - 0 (Benzophenanthridines)
RN  - 0 (Benzopyrans)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (RNA, Small Interfering)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - E29LP3ZMUH (rottlerin)
RN  - E3B045W6X0 (chelerythrine)
RN  - EC 2.7.10.1 (Receptor, trkA)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 3.4.22.- (Caspase 3)
RN  - SML2Y3J35T (Colchicine)
SB  - IM
CIN - Cell Res. 2009 May;19(5):525-6. PMID: 19421238
MH  - Acetophenones/pharmacology
MH  - Animals
MH  - *Apoptosis
MH  - Axonal Transport
MH  - Axons/*physiology
MH  - Benzophenanthridines/pharmacology
MH  - Benzopyrans/pharmacology
MH  - Caspase 3/metabolism
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Colchicine/pharmacology
MH  - Gene Knockdown Techniques
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Nerve Growth Factor/*physiology
MH  - Nerve Growth Factors/pharmacology
MH  - Neurons/physiology
MH  - Phosphorylation
MH  - Protein Kinase C/metabolism
MH  - Proto-Oncogene Proteins c-jun/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkA/metabolism
MH  - *Signal Transduction
MH  - Sympathetic Nervous System/cytology/*physiology
EDAT- 2009/02/04 09:00
MHDA- 2009/06/25 09:00
CRDT- 2009/02/04 09:00
PHST- 2009/02/04 09:00 [entrez]
PHST- 2009/02/04 09:00 [pubmed]
PHST- 2009/06/25 09:00 [medline]
AID - cr200911 [pii]
AID - 10.1038/cr.2009.11 [doi]
PST - ppublish
SO  - Cell Res. 2009 May;19(5):546-60. doi: 10.1038/cr.2009.11.