Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve

Tandrup, Trine; Woolf, Clifford J.; Coggeshall, Richard E.

doi:10.1002/(sici)1096-9861(20000626)422:2<172::aid-cne2>3.0.co;2-h

Cited by 202 publications

(134 citation statements)

References 65 publications

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“…S3E). These profile counts are similar to published approximations from both mice and rats (38,39). Given the lack of cell death and similar cell profile counts, the alteration of sensory subtypes in Gars C201R/+ DRG at 1 mo in vivo are consistent with a perturbation of neuronal fate.…”

Section: Gars C201r/+ Dorsal Root Ganglion Cultures Have a Smaller Pesupporting

confidence: 83%

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Sleigh

Dawes

West

et al. 2017

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

135

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Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.aminoacyl-tRNA synthetase | Charcot-Marie-Tooth disease | distal spinal muscular atrophy type V | neuromuscular disease | neurodevelopment C harcot-Marie-Tooth disease (CMT) is a group of genetically diverse peripheral neuropathies that share the main pathological feature of progressive motor and sensory degeneration (1). Although lifespan is usually unaffected, patients display characteristic muscle weakness and wasting predominantly in the extremities, leading to difficulty walking, foot deformities, and reduced dexterity (2). CMT is traditionally divided into type 1/ demyelinating CMTs that display loss of peripheral nerve myelin causing reduced nerve conduction velocity (NCV), type 2/axonal CMTs typified by axon loss with relatively normal NCVs, and intermediate CMTs that share clinical features of CMT1 and -2 (1). Over 80 different genetic loci have been linked to CMT, which is known to affect ∼1/2,500 people, making it the most common group of hereditary neuromuscular disorders (3).Dominant mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS, are causative of CMT type 2D (CMT2D) [Online Mendelian Inheritance in Man (OMIM) 601472], which normally manifests during adolescence and presents with muscle weakness in the extremities (4). The 2D subtype is one of a number of CMTs associated with mutation of an aminoacyl-tRNA synthetase (ARS) gene (5-8). Humans possess 37 ARS proteins, which covalently link amino acids to their partner transfer RNAs (tRNAs), thereby charging and priming the tRNAs for protein synthesis.This housekeeping function of gl...

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Section: Gars C201r/+ Dorsal Root Ganglion Cultures Have a Smaller Pesupporting

confidence: 83%

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Sleigh

Dawes

West

et al. 2017

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

135

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“…First, it is possible that reduced regeneration of dorsal column axons is attributable to cell loss and atrophy that might be associated with peripheral nerve axotomy (Knyihar-Csillik et al, 1987;Tandrup et al, 2000). To test this, we analyzed the viability of sensory neurons 5 weeks after sciatic axotomy (the time point used in this study) and revealed that there was no significant difference among all subpopulations of DRGs neurons between IL-6 ϩ/ϩ and Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Conditioning Injury-Induced Spinal Axon Regeneration Fails in Interleukin-6 Knock-Out Mice

Cafferty¹,

Gardiner²,

Das³

et al. 2004

J. Neurosci.

242

165

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Regeneration of injured adult sensory neurons within the CNS is essentially abortive, attributable in part to lesion-induced or revealed inhibitors such as the chondroitin sulfate proteoglycans and the myelin inhibitors (Nogo-A, MAG, and OMgp). Much of this inhibition may be overcome by boosting the growth status of sensory neurons by delivering a conditioning lesion to their peripheral branches. Here, we identify a key role for the lesion-induced cytokine interleukin-6 (IL-6) in mediating conditioning lesion-induced enhanced regeneration of injured dorsal column afferents. In adult mice, conditioning injury to the sciatic nerve 1 week before bilateral dorsal column crush resulted in regeneration of dorsal column axons up to and beyond the injury site into host CNS tissue. This enhanced growth state was accompanied by an increase in the expression of the growth-associated protein GAP43 in preinjured but not intact dorsal root ganglia (DRGs). Preconditioning injury of the sciatic nerve in IL-6 Ϫ/Ϫ mice resulted in the total failure in regeneration of dorsal column axons consequent on the lack of GAP43 upregulation after a preconditioning injury. DRGs cell counts and cholera toxin ␤ subunit labeling revealed that impaired regeneration in knock-out mice was unrelated to cell loss or a deficit in tracer transport. In vitro, exogenous IL-6 boosted sensory neuron growth status as evidenced by enhanced neurite extension. This effect required NGF or NT-3 but not soluble IL-6 receptor as cofactors. Evidence of conditioning lesion-enhanced growth status of DRGs cells can also be observed in vitro as an earlier and enhanced rate of neurite extension; this phenomenon fails in IL-6 Ϫ/Ϫ mice preinjured 7 d in vivo. We suggest that injury-induced IL-6 upregulation is required to promote regeneration within the CNS. Our results indicate that this is achieved through a boosted growth state of dorsal column projecting sensory neurons.

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“…The number of primary sensory neurons decreases late (Ͼ8 weeks) after axotomy (Tandrup et al, 2000). There is no loss of monosynaptic excitatory currents in lamina II neurons (Moore et al, 2002), and polysynaptic afferent input actually increases after SNI .…”

Section: Blocking Apoptosis Prevents the Loss Of Spinal Inhibitionmentioning

confidence: 97%

Blocking Caspase Activity Prevents Transsynaptic Neuronal Apoptosis and the Loss of Inhibition in Lamina II of the Dorsal Horn after Peripheral Nerve Injury

et al. 2005

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We show that transsynaptic apoptosis is induced in the superficial dorsal horn (laminas I-III) of the spinal cord by three distinct partial peripheral nerve lesions: spared nerve injury, chronic constriction, and spinal nerve ligation. Ongoing activity in primary afferents of the injured nerve and glutamatergic transmission cause a caspase-dependent degeneration of dorsal horn neurons that is slow in onset and persists for several weeks. Four weeks after spared nerve injury, the cumulative loss of dorsal horn neurons, determined by stereological analysis, is Ͼ20%.

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Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve

Cited by 202 publications

References 65 publications

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Conditioning Injury-Induced Spinal Axon Regeneration Fails in Interleukin-6 Knock-Out Mice

Blocking Caspase Activity Prevents Transsynaptic Neuronal Apoptosis and the Loss of Inhibition in Lamina II of the Dorsal Horn after Peripheral Nerve Injury

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