Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation

Abstract

Several experimental manipulations of the CNS environment successfully elicit regeneration of sensory and bulbospinal motor axons but fail to elicit regeneration of corticospinal axons, suggesting that cell-intrinsic mechanisms limit the regeneration of this critical class of motor neurons. We hypothesized that enhancement of intrinsic neuronal growth mechanisms would enable adult corticospinal motor axon regeneration. Lentiviral vectors were used to overexpress the BDNF receptor trkB in layer V corticospinal motor neurons. After subcortical axotomy, trkB transduction induced corticospinal axon regeneration into subcortical lesion sites expressing BDNF. In the absence of trkB overexpression, no regeneration occurred. Selective deletion of canonical, trkB-mediated neurite outgrowth signaling by mutation of the Shc/FRS-2 activation domain prohibited Erk activation and eliminated regeneration. These findings support the hypothesis that the refractory regenerative state of adult corticospinal axons can be attributed at least in part to neuron-intrinsic mechanisms, and that activation of ERK signaling can elicit corticospinal tract regeneration.BDNF ͉ intrinsic ͉ retrograde infection ͉ subcortical lesion

Dock3 regulates BDNF‐TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG

“…Consistent with previous studies (Hollis et al 2009), TrkB is required for BDNF-mediated neurite outgrowth in PC12 cells (Fig. 4A).…”

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

“…Mice lacking PTEN are able to regenerate axons following optic nerve crush and exhibit sprouting of corticospinal axons after injury, similar to observations after NT-3 delivery to the injured spinal cord [136,137]. Studies with NT-3 and PTEN underscore that attempts to promote corticospinal regeneration may require not only modulation of the injured environment, but also the intrinsic growth state of injured neurons [132,136].…”

“…These studies focused on manipulation of the cellular response in neurons that are already able to regenerate; however, a similar approach has also been used to alter the response of the more refractory corticospinal motor neurons. Viral delivery of the high affinity BDNF neurotrophin receptor trkB to the motor cortex, resulting in over-expression of trkB, can alter the response of cortical neurons and corticospinal motor neurons in particular to BDNF-secreting grafts [132]. Over-expressed trkB is trafficked into the axonal compartment of identified corticospinal neurons and results in regeneration of transduced neurons into subcortical BDNFsecreting grafts through Erk/Map kinase pathways [132].…”

“…Viral delivery of the high affinity BDNF neurotrophin receptor trkB to the motor cortex, resulting in over-expression of trkB, can alter the response of cortical neurons and corticospinal motor neurons in particular to BDNF-secreting grafts [132]. Over-expressed trkB is trafficked into the axonal compartment of identified corticospinal neurons and results in regeneration of transduced neurons into subcortical BDNFsecreting grafts through Erk/Map kinase pathways [132]. Trafficking of the receptor is limited, however, as virally expressed trkB is undetectable in the spinal cord [132].…”

“…Over-expressed trkB is trafficked into the axonal compartment of identified corticospinal neurons and results in regeneration of transduced neurons into subcortical BDNFsecreting grafts through Erk/Map kinase pathways [132]. Trafficking of the receptor is limited, however, as virally expressed trkB is undetectable in the spinal cord [132]. One of the downstream mediators of neurotrophin signaling is phosphoinositide 3-kinase, which signals through the serinethreonine kinase Akt, a process inhibited by phosphotase and tensin homologue (PTEN) [133][134][135].…”