Imperial College London
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ProfessorSimoneDi Giovanni

Faculty of Medicine, Department of Brain Sciences

James W Harnett Chair in Restorative Neuroscience
 
 
 
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Contact

 

+44 (0)20 7594 3178s.di-giovanni

 
 
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Location

 

E505Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hervera:2019:10.15252/embj.2018101032,
author = {Hervera, A and Zhou, L and Palmisano, I and McLachlan, E and Kong, G and Hutson, TH and Danzi, MC and Lemmon, VP and Bixby, JL and Matamoros-Angles, A and Forsberg, K and De, Virgiliis F and Matheos, DP and Kwapis, J and Wood, MA and Puttagunta, R and Del, Río JA and Di, Giovanni S},
doi = {10.15252/embj.2018101032},
journal = {EMBO Journal},
title = {PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure},
url = {http://dx.doi.org/10.15252/embj.2018101032},
volume = {38},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regenerationcompetent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regenerationincompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with smallmolecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.
AU  - Hervera,A
AU  - Zhou,L
AU  - Palmisano,I
AU  - McLachlan,E
AU  - Kong,G
AU  - Hutson,TH
AU  - Danzi,MC
AU  - Lemmon,VP
AU  - Bixby,JL
AU  - Matamoros-Angles,A
AU  - Forsberg,K
AU  - De,Virgiliis F
AU  - Matheos,DP
AU  - Kwapis,J
AU  - Wood,MA
AU  - Puttagunta,R
AU  - Del,Río JA
AU  - Di,Giovanni S
DO  - 10.15252/embj.2018101032
PY  - 2019///
SN  - 0261-4189
TI  - PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure
T2  - EMBO Journal
UR  - http://dx.doi.org/10.15252/embj.2018101032
UR  - http://hdl.handle.net/10044/1/70243
VL  - 38
ER  -
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