Signaling the Pathway to Regeneration

Snider, William D.; Zhou, Feng; Zhong, Jian; Markus, Annette

doi:10.1016/s0896-6273(02)00762-6

Cited by 136 publications

(86 citation statements)

References 24 publications

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“…Second, OMP-positive ORNs with functional, reinforced synapses are less dependent on target-derived trophic support, can use truncated TrkB to protect from p75 stimulation, and exhibit a greater dependence on afferent odor stimulation (Watt et al, 2004) and support from olfactory ensheathing cells (OECs) of the nerve fiber layer (Woodhall et al, 2001;Lipson et al, 2003). In the absence of proapoptotic signals, persistent OMP-positive axons represent the most stable ORNs able to combine activity and OEC-derived signals to remain and form new targets, similar to many central neurons after injury (Snider et al, 2002). Third, the final subpopulation of ORNs likely represents a malfunctioning ("molecularly senescent") ORN population, with a higher potential to amplify localized synaptic caspase activation and initiate retrograde apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Axonal Dynactin p150^GluedTransports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis

Carson

Saleh²,

Nicholson³

et al. 2005

J. Neurosci.

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Olfactory receptor neurons (ORNs) undergo caspase-mediated retrograde apoptosis after target removal (bulbectomy), in which axonal caspase-9 and caspase-3 activation leads to terminal apoptosis in ORN soma of the olfactory epithelium. Here, we show that caspase-8 can act as an initiator of ORN apoptosis after bulbectomy and also after synaptic instability is induced by NMDA-mediated excitotoxic death of ORN target neurons in the olfactory bulb. Caspase-8 and caspase-3 are sequentially activated within ORN presynaptic terminals, and caspase-8 complexes with dynactin p150Glued , (a retrograde motor protein) and is transported retrogradely, preceding axonal caspase-3 activation and apoptosis of ORN cell bodies. Focal in vivo inhibition of initiator caspase activation or microtubule-dependent transport (with Taxol) at the lesioned axon terminus results in a significant reduction in retrograde axonal caspase-8 and caspase-3 activation and inhibition of retrograde ORN death. Caspase-8 activation and retrograde transport after NMDA lesion is similarly reduced in mice null for p75, the low-affinity nerve growth factor receptor. The retrograde apoptosis of ORNs thus involves a novel mechanism that used p75 in the local activation of caspase-8. Once caspase-8 is maximally activated in the presynaptic terminal, it is transported retrogradely by the motor complex dynactin/dynein, a process that can be inhibited focally to inhibit ORN apoptosis after acute axonal lesion. These data have revealed a novel mechanism of retrograde apoptosis, in which caspase-8 complexes directly with axonal dynactin p150Glued to reveal a differential vulnerability of subpopulations of ORNs to undergo apoptosis after axonal damage and the loss of olfactory bulb target neurons.

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Section: Discussionmentioning

confidence: 99%

Axonal Dynactin p150^GluedTransports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis

Carson

Saleh²,

Nicholson³

et al. 2005

J. Neurosci.

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“…As an injury ensues, the signal is sensed by nearby Schwann cells, which then produce and release neurotrophins that promote regeneration of the injured axon. [2][3][4] Four neurotrophins have been characterized in mammals: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Although similar in sequence and structure, different neurotrophins play distinctive roles during neuronal development and regeneration.…”

Section: Introductionmentioning

confidence: 99%

Growth factor therapy and neuronal nitric oxide synthase

Lin

2004

Int J Impot Res

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Trauma to the cavernous nerve is a known cause of erectile dysfunction, with lengthy and often incomplete recovery. Using rat models, we have previously shown that injury to the cavernous nerves or ligation of pudendal arteries causes a significant decrease of neuronal nitric oxide synthase (nNOS) in the dorsal nerve of the penis and intracavernosal tissue as well as loss of erectile response to neurostimulation. Intracavernous injection of vascular endothelial growth factor or brain-derived neurotrophic factor facilitates the recovery of nNOS and erectile function. Studies are underway to elucidate the molecular mechanism of cavernous nerve regeneration and the potential of using growth factors to enhance the recovery of erectile function in patients after radical pelvic surgery.

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“…The ability of adult neurons of the CNS to regenerate their axons in response to injury is limited in many neuronal types depending on both intrinsic and extrinsic factors (3)(4)(5)(6)(7)(8). Axons in the CNS represent a challenging site for targeted manipulation and in vivo imaging, and little is known about their postlesional reactive plasticity and how this is regulated by molecular mediators.…”

mentioning

confidence: 99%

In vivo single branch axotomy induces GAP-43–dependent sprouting and synaptic remodeling in cerebellar cortex

Mascaro

Cesare

Sacconi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

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Plasticity in the central nervous system in response to injury is a complex process involving axonal remodeling regulated by specific molecular pathways. Here, we dissected the role of growthassociated protein 43 (GAP-43; also known as neuromodulin and B-50) in axonal structural plasticity by using, as a model, climbing fibers. Single axonal branches were dissected by laser axotomy, avoiding collateral damage to the adjacent dendrite and the formation of a persistent glial scar. Despite the very small denervated area, the injured axons consistently reshape the connectivity with surrounding neurons. At the same time, adult climbing fibers react by sprouting new branches through the intact surroundings. Newly formed branches presented varicosities, suggesting that new axons were more than just exploratory sprouts. Correlative light and electron microscopy reveals that the sprouted branch contains large numbers of vesicles, with varicosities in the close vicinity of Purkinje dendrites. By using an RNA interference approach, we found that downregulating GAP-43 causes a significant increase in the turnover of presynaptic boutons. In addition, silencing hampers the generation of reactive sprouts. Our findings show the requirement of GAP-43 in sustaining synaptic stability and promoting the initiation of axonal regrowth.brain injury | two-photon imaging | neural plasticity | laser nanosurgery

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Signaling the Pathway to Regeneration

Cited by 136 publications

References 24 publications

Axonal Dynactin p150^GluedTransports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis

Axonal Dynactin p150^GluedTransports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis

Growth factor therapy and neuronal nitric oxide synthase

In vivo single branch axotomy induces GAP-43–dependent sprouting and synaptic remodeling in cerebellar cortex

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Signaling the Pathway to Regeneration

Cited by 136 publications

References 24 publications

Axonal Dynactin p150GluedTransports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis

Axonal Dynactin p150GluedTransports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis

Growth factor therapy and neuronal nitric oxide synthase

In vivo single branch axotomy induces GAP-43–dependent sprouting and synaptic remodeling in cerebellar cortex

Contact Info

Product

Resources

About

Axonal Dynactin p150^GluedTransports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis

Axonal Dynactin p150^GluedTransports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis