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PP4‐dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure
Author(s) -
Hervera Arnau,
Zhou Luming,
Palmisano Ilaria,
McLachlan Eilidh,
Kong Guiping,
Hutson Thomas H,
Danzi Matt C,
Lemmon Vance P,
Bixby John L,
MatamorosAngles Andreu,
Forsberg Kirsi,
De Virgiliis Francesco,
Matheos Dina P,
Kwapis Janine,
Wood Marcelo A,
Puttagunta Radhika,
del Río José Antonio,
Di Giovanni Simone
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018101032
Subject(s) - neuroregeneration , neuroscience , brain research , regeneration (biology) , library science , medicine , biology , neuroprotection , computer science , genetics
Abstract The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration‐competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia ( DRG ) sensory neurons, a regeneration‐incompetent 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 small‐molecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC 3 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 HDAC 3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac Ch IP seq and RNA seq from DRG followed by promoter acetylation and protein expression studies implicated HDAC 3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC 3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP 4‐dependent HDAC 3 dephosphorylation discriminates between axonal regeneration and regenerative failure.