A monoclonal antibody against neurofilament protein specifically labels a subpopulation of rat sensory neurones

Lawson, Sally N.; Harper, A. A.; Harper, Ei; Garson, Jeremy A.; Anderton, Brian H.

doi:10.1002/cne.902280211

Cited by 303 publications

(164 citation statements)

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“…S2A), often described as A fibers (33). Corroborating the cell body measurements, Gars C201R/+ cultures had a significantly smaller percentage of βIII-tubulin + cells (green) that expressed NF200 (red) than wild type ( Fig.…”

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

confidence: 71%

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 Pementioning

confidence: 71%

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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“…3A). Neurofilament content can distinguish ϳ40% of lumbar DRG neurons that often are of large diameter (Lawson et al, 1984;Lawson and Waddell, 1991;Perry et al, 1991). Two antibodies were used to assay neurofilament: one that recognizes the intermediate molecular weight isoform (NF-M) and a second that recognizes the high molecular weight isoform only when phosphorylated (NF-H-PO 4 ), and similar results were obtained.…”

Section: Neuropeptide-and Neurofilament-containing Drg Neurons Develomentioning

confidence: 71%

“…Neuropeptides are often found in small DRG neurons that can innervate skin and viscera, whereas abundant neurofilament expression is characteristic of large neurons that innervate muscle spindles (Lawson et al, 1984;Perry et al, 1991). The neuropeptides CGRP and substance P are usually found in small neurons but can be contained in sensory neurons of varied sizes (Gibson et al, 1984;Lee et al, 1985;Skofitsch and Jacobowitz, 1985;Gibbins et al, 1987;Marti et al, 1987;Molander et al, 1987;Lawson, 1989, 1990;O'Brien et al, 1989).…”

mentioning

confidence: 99%

The Generation of Neuronal Heterogeneity in a Rat Sensory Ganglion

Hall

Hickman

et al. 1997

J. Neurosci.

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Adult sensory neurons differ chemically, morphologically, and functionally, but the factors that generate their diversity remain unclear. For example, neuropeptides are generally found in small neurons, whereas abundant neurofilament is common in large neurons. Neurons containing the neuropeptides calcitonin gene-related peptide (CGRP) or substance P were quantified using immunohistochemistry in rat lumbar dorsal root ganglion (DRG) at times before and after sensory neurons contact central and peripheral targets in vivo. No neurons in the newly formed DRG expressed neuropeptide or neuropeptide mRNA, but neuropeptides were detectable about the time that axons connect with peripheral targets. To determine the requirement for target in neuropeptide regulation, embryonic DRG neurons were isolated at times before central and peripheral connections had formed, placed in culture, and immunocytochemically assayed for CGRP and substance P. Cultured neurons expressed neuropeptides with a time course and in proportions similar to those in vivo. Thus, some neurons in the embryonic DRG seem to be intrinsically specified to later express CGRP and substance P. The percentage of CGRP-immunoreactive neurons was not changed by cell density, non-neuronal cells, neurotrophins in addition to nerve growth factor (NGF), or antibody inactivation of neurotrophin-3 in the presence of NGF. To test the role of extrinsic cues on CGRP expression, DRG neurons were co-cultured with potential target tissues. Coculture with a rat epidermal or smooth muscle cell line increased the proportion of CGRP-containing neurons, whereas primary skeletal muscle and 3T3 cells had no effects. Thus, multiple appropriate sensory neuron phenotypes arise in a regulated fashion in cultured neurons isolated before target connections have formed, and some candidate target tissues can modulate that intrinsic expression pattern. Key words: neuropeptides; substance P; calcitonin generelated peptide; neurofilament; nociceptive; sensory ganglion; target tissue; skin; neurotrophinA striking feature of the adult vertebrate sensory nervous system is the diversity of neuronal cell types that perform together to maintain homeostasis and convey information about the environment. During development, specific neurons must be generated in appropriate locations and connect discretely to both peripheral targets and the CNS for functional integrity. Thus, it is important to understand not only how the phenotype is generated but also how neurons match targets. This study examines the developmental regulation of sensory neurons containing calcitonin generelated peptide (CGRP) that predominantly contact visceral and cutaneous peripheral target end organs in vivo.Adult rat sensory neurons can express neuromodulatory neuropeptides, but the factors that regulate their initial expression remain unknown. Cutaneous afferents appear in rat proximal hindlimb on embryonic days 14 -15 (E14 -E15) and in skin of distal toes at E16 -E17 (Reynolds et al

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“…One important difference is the amount of neurofilament, since LLN contain huge amounts of NfH and the SDN do not [28,29]. In WR DRG (Figure 2A) and control DRG ( Figure 2G) stained for NfH, no light microscopic differences could be detected.…”

Section: Neurofilament Disarrangement In the Wobbler Mousementioning

confidence: 93%

Morphological Studies of Wobbler Mouse Dorsal Root Ganglia Show Neurofilamental Disorders

Ott¹,

Dahlke²,

Saberi³

et al. 2017

J Neurol Exp Neurosci

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with three described forms: The abundant, sporadic ALS (sALS) with approximately 90% of cases, the familial ALS (fALS) with 5-10%, and the very rare juvenile ALS (jALS) group, which is statistically less relevant. The wobbler mouse, a model for sALS, has been in the focus of research for many decades. Due to symptoms strongly resembling the human ALS pathology, the α-motor neurons (αMN) have received the most attention. With regard to pathological cellular processes, particularly those of impaired axonal transport, neuronal tissues in general should be examined. Dorsal root ganglia (DRG) cells are equipped with extremely long axons. Thus, we expected them to be an excellent target for analyzing the cellular mechanisms underlying the disease. In this study, an analysis of the distribution of heavy neurofilaments (NfH) in the perikarya and peripheral nerves of dorsal root ganglia cells from wobbler mice was performed. Here, we demonstrate that sensory neurons are also affected in wobbler mice during the progression of the disease, showing signs of degeneration like those described in the αMN. Furthermore, a highly impaired distribution of neurofilaments and a high number of phosphorylated heavy neurofilaments (pNfH) were observed, not only in large light neurons (LLN), but also in the small dark neurons (SDN) of wobbler mouse DRGs. The accumulation of pNfH in DRG as well as the loss of NfH in their axons are promising links to studies promoting high levels of pNfH in the cerebrospinal fluid (CSF) as an early hallmark of ALS in humans. KeywordsDorsal root ganglia, Amyotrophic lateral sclerosis, Wobbler, Neurofilaments, Neurodegeneration IntroductionNeurological diseases, and in particular motor neuron diseases (MND), have a great impact on a patient's quality of life. ALS is a common MND with an incidence of 1-3 cases per 100.000 per year and a prevalence of 3-8 per 100.000, with men being more often affected than women. The average survival is 3 years after the onset of ALS symptoms, typically between the ages of 55 to 60 [1]. Many pathological mechanisms have already been well investigated in animal models with ALS-like phenotypes, however comparison to the human ALS pathology is difficult. A treatment substantially modifying the diseases progression is still lacking. The well-known degeneration of the upper and lower motor neurons are common in the murine models as well as in humans. This

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A monoclonal antibody against neurofilament protein specifically labels a subpopulation of rat sensory neurones

Cited by 303 publications

References 15 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

The Generation of Neuronal Heterogeneity in a Rat Sensory Ganglion

Morphological Studies of Wobbler Mouse Dorsal Root Ganglia Show Neurofilamental Disorders

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