PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons.
In vivo regeneration of peripheral neurons is constrained and rarely complete, and unfortunately patients with major nerve trunk transections experience only limited recovery. Intracellular inhibition of neuronal growth signals may be among these constraints. In this work, we investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during regeneration of peripheral neurons in adult Sprague Dawley rats. PTEN inhibits phosphoinositide 3-kinase (PI3-K)/Akt signaling, a common and central outgrowth and survival pathway downstream of neuronal growth factors. While PI3-K and Akt outgrowth signals were expressed and activated within adult peripheral neurons during regeneration, PTEN was similarly expressed and poised to inhibit their support. PTEN was expressed in neuron perikaryal cytoplasm, nuclei, regenerating axons, and Schwann cells. Adult sensory neurons in vitro responded to both graded pharmacological inhibition of PTEN and its mRNA knockdown using siRNA. Both approaches were associated with robust rises in the plasticity of neurite outgrowth that were independent of the mTOR (mammalian target of rapamycin) pathway. Importantly, this accelerated outgrowth was in addition to the increased outgrowth generated in neurons that had undergone a preconditioning lesion. Moreover, following severe nerve transection injuries, local pharmacological inhibition of PTEN or siRNA knockdown of PTEN at the injury site accelerated axon outgrowth in vivo. The findings indicated a remarkable impact on peripheral neuron plasticity through PTEN inhibition, even within a complex regenerative milieu. Overall, these findings identify a novel route to propagate intrinsic regeneration pathways within axons to benefit nerve repair.
Christie
Kimberly J
KJ
Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Webber
Christine A
CA
Martinez
Jose A
JA
Singh
Bhagat
B
Zochodne
Douglas W
DW
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006023:Glycoproteins / Q000378:metabolism; D008297:Male; D009416:Nerve Regeneration / Q000502:physiology*; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012337:RNA, Ribosomal, 18S / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D006023:Glycoproteins; D016900:Neurofilament Proteins; D009942:Organometallic Compounds; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; D034741:RNA, Small Interfering; C473590:isolectin B4-binding glycoprotein, mouse; C119540:oxodiperoxo(pyridine-2-carboxylate)vanadate(V); C051774:neurofilament protein H; D000071679:Glycogen Synthase Kinase 3 beta; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat