TY - JOUR
T1 - STAT3 integrates cytokine and neurotrophin signals to promote sympathetic axon regeneration
AU - Pellegrino, Michael J.
AU - Habecker, Beth A.
N1 - Funding Information:
This work was supported by R01 HL068231 & HL093056 ( BAH ) and NINDS P30 Center Grant (Jungers Center-OHSU). The authors thank Diana Parrish, Eric Alston, and Dr. Xiao Shi for technical assistance, and thank Dr. Richard Zigmond and Jon Niemi for comments on the manuscript. After this work was completed, we were informed by Addgene (Cambridge, MA) that STAT3-WT (pcDNA3), a construct we purchased from them, had a mutation in the open reading frame resulting in an amino acid change (E16K). We compared results to another plasmid (STAT3-WT Flag pRc/CMV) and saw no difference.
PY - 2013/9
Y1 - 2013/9
N2 - The transcription factor STAT3 has been implicated in axon regeneration. Here we investigate a role for STAT3 in sympathetic nerve sprouting after myocardial infarction (MI) - a common injury in humans. We show that NGF stimulates serine phosphorylation (S727) of STAT3 in sympathetic neurons via ERK1/2, in contrast to cytokine phosphorylation of Y705. Maximal sympathetic axon regeneration in vitro requires phosphorylation of both S727 and Y705. Furthermore, cytokine signaling is necessary for NGF-induced sympathetic nerve sprouting in the heart after MI. Transfection studies in neurons lacking STAT3 suggest two independent pools of STAT3, phosphorylated on either S727 or Y705, that regulate sympathetic regeneration via both transcriptional and non-transcriptional means. Additional data identify STAT3-microtubule interactions that may complement the well-characterized role of STAT3 stimulating regeneration associated genes. These data show that STAT3 is critical for sympathetic axon regeneration in vitro and in vivo, and identify a novel non-transcriptional mode of action.
AB - The transcription factor STAT3 has been implicated in axon regeneration. Here we investigate a role for STAT3 in sympathetic nerve sprouting after myocardial infarction (MI) - a common injury in humans. We show that NGF stimulates serine phosphorylation (S727) of STAT3 in sympathetic neurons via ERK1/2, in contrast to cytokine phosphorylation of Y705. Maximal sympathetic axon regeneration in vitro requires phosphorylation of both S727 and Y705. Furthermore, cytokine signaling is necessary for NGF-induced sympathetic nerve sprouting in the heart after MI. Transfection studies in neurons lacking STAT3 suggest two independent pools of STAT3, phosphorylated on either S727 or Y705, that regulate sympathetic regeneration via both transcriptional and non-transcriptional means. Additional data identify STAT3-microtubule interactions that may complement the well-characterized role of STAT3 stimulating regeneration associated genes. These data show that STAT3 is critical for sympathetic axon regeneration in vitro and in vivo, and identify a novel non-transcriptional mode of action.
KW - Ciliary neurotrophic factor
KW - Myocardial infarction
KW - Nerve growth factor
KW - Signal transducer and activator of transcription 3
KW - Sympathetic axon regeneration
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U2 - 10.1016/j.mcn.2013.06.005
DO - 10.1016/j.mcn.2013.06.005
M3 - Article
C2 - 23831387
AN - SCOPUS:84880940533
SN - 1044-7431
VL - 56
SP - 272
EP - 282
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
ER -