Phosphorylation of STAT3 by axonal Cdk5 promotes axonal regeneration by modulating mitochondrial activity

Copyright © 2020 Elsevier Inc. All rights reserved..

Cyclin-dependent kinase 5 (Cdk5) is involved in neural organization and synaptic functions in developing and adult brains, yet its role in axonal regeneration is not known well. Here, we characterize Cdk5 function for axonal regeneration after peripheral nerve injury. Levels of Cdk5 and p25 were elevated in sciatic nerve axons after injury. Cdk5 activity was concomitantly induced from injured nerve and increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) on the serine 727 residue. Pharmacological and genetic blockades of Cdk5 activity phosphorylating STAT3 resulted in the inhibition of axonal regeneration as evidenced by reduction of retrograde labeling of dorsal root ganglion (DRG) sensory neurons and spinal motor neurons and also of neurite outgrowth of preconditioned DRG neurons in culture. Cdk5 and STAT3 were found in mitochondrial membranes of the injured sciatic nerve. Cdk5-GFP, which was translocated into the mitochondria by the mitochondrial target sequence (MTS), induced STAT3 phosphorylation in transfected DRG neurons and was sufficient to induce neurite outgrowth. In the mitochondria, Cdk5 activity was positively correlated with increased mitochondrial membrane potential as measured by fluorescence intensity of JC-1 aggregates. Our data suggest that Cdk5 may play a role in modulating mitochondrial activity through STAT3 phosphorylation, thereby promoting axonal regeneration.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:335

Enthalten in:

Experimental neurology - 335(2021) vom: 01. Jan., Seite 113511

Sprache:

Englisch

Beteiligte Personen:

Hwang, Jinyeon [VerfasserIn]
Namgung, Uk [VerfasserIn]

Links:

Volltext

Themen:

Axon
Cdk5 protein, rat
Cyclin-Dependent Kinase 5
Cyclin-dependent kinase 5
EC 2.7.11.1
EC 2.7.11.22
Journal Article
Mitochondria
Regeneration
Research Support, Non-U.S. Gov't
STAT3
STAT3 Transcription Factor
Sciatic nerve
Stat3 protein, rat

Anmerkungen:

Date Completed 19.04.2021

Date Revised 19.04.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.expneurol.2020.113511

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM316677108