Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor for sensory neurons: Comparison with the effects of the neurotrophins

Matheson, Christine R.; Carnahan, Josette; Urich, Janal L.; Bocangel, Dora; Zhang, T. J.; Qiao, Yan

doi:10.1002/(sici)1097-4695(199701)32:1<22::aid-neu3>3.0.co;2-g

Cited by 121 publications

(49 citation statements)

References 39 publications

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“…7b). We obtained similar data for radiolabeled NT-3, consistent with its known transport along the sciatic nerve (Matheson et al, 1997). The amount of GDF-15 that is transported (3-4 pg) appears to be similar to that of NT-3 (data not shown).…”

Section: Resultssupporting

confidence: 75%

“…While we failed to observe retrograde transport from injections into transected nerves to DRGs or motoneurons in the spinal cord (data not shown), we observed significant accumulation and transport of GDF-15 in ligated sciatic nerves. In the ligation experiments, NT-3 was used as a positive control, since it is known to be transported retrogradely in the sciatic nerve (Matheson et al, 1997). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Some growth factors such as CNTF (Curtis et al, 1993) are poorly transported axonally, while others are very efficiently transported retrogradely along axons (Matheson et al, 1997; Rind et al, 2005). To determine whether GDF-15 is axonally transported, we pursued two strategies: direct application of radiolabeled GDF-15 to the transected sciatic nerve stump (Leitner et al, 1999) followed by autoradiography of DRGs and spinal cord sections, and measurement of accumulation of radiolabeled GDF-15 distal to a sciatic nerve ligation.…”

Section: Discussionmentioning

confidence: 99%

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Progressive Postnatal Motoneuron Loss in Mice Lacking GDF-15

Strelau¹,

et al. 2009

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GDF-15 is a widely expressed distant member of the TGF-ß superfamily with prominent neurotrophic effects on midbrain dopaminergic neurons. We show here that GDF-15 deficient mice exhibit progressive postnatal losses of spinal, facial, and trigeminal motoneurons. This deficit reaches a ~20% maximum at 6 months and is accompanied by losses of motor axons and significant impairment of rotarod skills. Similarly, sensory neurons in dorsal root ganglia (L4, L5) are reduced by 20%, while sympathetic neurons are not affected. GDF-15 is expressed and secreted by Schwann cells, retrogradely transported along adult sciatic nerve axons, and promotes survival of axotomized facial neurons as well as cultured motor, sensory, and sympathetic neurons. Despite striking similarities in the GDF-15 and CNTF knockout phenotypes, expression levels of CNTF and other neurotrophic factors in the sciatic nerve were unaltered suggesting that GDF-15 is a genuine novel trophic factor for motor and sensory neurons.

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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Progressive Postnatal Motoneuron Loss in Mice Lacking GDF-15

Strelau¹,

et al. 2009

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“…Importantly, and in-line with the neurotrophic hypothesis, these changes are mimicked by depletion of the relevant factors in the absence of axotomy, and reversed by supplying axotomized neurons with trophic support from exogenous sources (Rich et al, 1984; Yip et al, 1984; Johnson and Yip, 1985; Wong and Oblinger, 1991; Matheson et al, 1997; Bennett et al, 1998). Uninjured DRG neurons undergo hypertrophy following in vivo delivery of NGF or GDNF (Ramer et al, 2001, 2003).…”

Section: Introductionmentioning

confidence: 82%

Plasticity of TRPV1-Expressing Sensory Neurons Mediating Autonomic Dysreflexia Following Spinal Cord Injury

Ramer¹,

Stolk²,

Inskip³

et al. 2012

Front. Physio.

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Spinal cord injury (SCI) triggers profound changes in visceral and somatic targets of sensory neurons below the level of injury. Despite this, little is known about the influence of injury to the spinal cord on sensory ganglia. One of the defining characteristics of sensory neurons is the size of their cell body: for example, nociceptors are smaller in size than mechanoreceptors or proprioceptors. In these experiments, we first used a comprehensive immunohistochemical approach to characterize the size distribution of sensory neurons after high- and low-thoracic SCI. Male Wistar rats (300 g) received a spinal cord transection (T3 or T10) or sham-injury. At 30 days post-injury, dorsal root ganglia (DRGs) and spinal cords were harvested and analyzed immunohistochemically. In a wide survey of primary afferents, only those expressing the capsaicin receptor (TRPV1) exhibited somal hypertrophy after T3 SCI. Hypertrophy only occurred caudal to SCI and was pronounced in ganglia far distal to SCI (i.e., in L4-S1 DRGs). Injury-induced hypertrophy was accompanied by a small expansion of central territory in the lumbar spinal dorsal horn and by evidence of TRPV1 upregulation. Importantly, hypertrophy of TRPV1-positive neurons was modest after T10 SCI. Given the specific effects of T3 SCI on TRPV1-positive afferents, we hypothesized that these afferents contribute to autonomic dysreflexia (AD). Rats with T3 SCI received vehicle or capsaicin via intrathecal injection at 2 or 28 days post-SCI; at 30 days, AD was assessed by recording intra-arterial blood pressure during colo-rectal distension (CRD). In both groups of capsaicin-treated animals, the severity of AD was dramatically reduced. While AD is multi-factorial in origin, TRPV1-positive afferents are clearly involved in AD elicited by CRD. These findings implicate TRPV1-positive afferents in the initiation of AD and suggest that TRPV1 may be a therapeutic target for amelioration or prevention of AD after high SCI.

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“…Indeed, GDNF (glial cell-derived neurotrophic factor) promotes the axon development and the survival of sensory neurons at different stages of the development in mice and chicken model [22–25]. Moreover, it has been shown in vitro that after injury, nearly 100% of the sensory neurons are rescued by the production or injection of GDNF [24,46,52,53]. We thus expected that this AMS variant could disturb the expression of GDNF leading to the decrease of the number of sensory neurons and then their death, as previously observed in affected dogs [18–20].…”

Section: Discussionmentioning

confidence: 99%

A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies

Plassais¹,

Lagoutte²,

Correard³

et al. 2016

PLoS Genet

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Human Hereditary Sensory Autonomic Neuropathies (HSANs) are characterized by insensitivity to pain, sometimes combined with self-mutilation. Strikingly, several sporting dog breeds are particularly affected by such neuropathies. Clinical signs appear in young puppies and consist of acral analgesia, with or without sudden intense licking, biting and severe self-mutilation of the feet, whereas proprioception, motor abilities and spinal reflexes remain intact. Through a Genome Wide Association Study (GWAS) with 24 affected and 30 unaffected sporting dogs using the Canine HD 170K SNP array (Illumina), we identified a 1.8 Mb homozygous locus on canine chromosome 4 (adj. p-val = 2.5x10-6). Targeted high-throughput sequencing of this locus in 4 affected and 4 unaffected dogs identified 478 variants. Only one variant perfectly segregated with the expected recessive inheritance in 300 sporting dogs of known clinical status, while it was never present in 900 unaffected dogs from 130 other breeds. This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in a long intergenic non-coding RNAs (lincRNA), GDNF-AS. Using human comparative genomic analysis, we observed that the canine variant maps onto an enhancer element. Quantitative RT-PCR of dorsal root ganglia RNAs of affected dogs showed a significant decrease of both GDNF mRNA and GDNF-AS expression levels (respectively 60% and 80%), as compared to unaffected dogs. We thus performed gel shift assays (EMSA) that reveal that the canine variant significantly alters the binding of regulatory elements. Altogether, these results allowed the identification in dogs of GDNF as a relevant candidate for human HSAN and insensitivity to pain, but also shed light on the regulation of GDNF transcription. Finally, such results allow proposing these sporting dog breeds as natural models for clinical trials with a double benefit for human and veterinary medicine.

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Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor for sensory neurons: Comparison with the effects of the neurotrophins

Cited by 121 publications

References 39 publications

Progressive Postnatal Motoneuron Loss in Mice Lacking GDF-15

Progressive Postnatal Motoneuron Loss in Mice Lacking GDF-15

Plasticity of TRPV1-Expressing Sensory Neurons Mediating Autonomic Dysreflexia Following Spinal Cord Injury

A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies

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