Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system

Schack, David von; Casademunt, Elisabeth; Schweigreiter, Rüdiger; Meyer, Michaël; Bibel, Miriam; Dechant, Georg

doi:10.1038/nn730

Cited by 235 publications

(229 citation statements)

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“…However, the mutant mice still express the splice variant of p75 NTR that retains CRD1 (53). Because CRD1 is sufficient for RVG binding (30), we repeated the experiment in mutant mice lacking exon IV (p75 NTR e xonIVϪ/Ϫ ) and thus all extracellular domains of the receptor (53). Again, these animals showed a clinical course similar to that in previous experiments and died in the same time period as wild-type animals.…”

Section: Resultsmentioning

confidence: 90%

“…In agreement with previously published work (25), the clinical course of the disease was similar in both strains, with the first symptoms appearing 4 to 5 days after inoculation and all animals dying within 2 weeks. However, the mutant mice still express the splice variant of p75 NTR that retains CRD1 (53). Because CRD1 is sufficient for RVG binding (30), we repeated the experiment in mutant mice lacking exon IV (p75 NTR e xonIVϪ/Ϫ ) and thus all extracellular domains of the receptor (53).…”

Section: Resultsmentioning

confidence: 99%

“…Mutant mice lacking exon III (p75 NTRExonIIIϪ/Ϫ ) (34) were obtained from Jackson Laboratories (Bar Harbor, ME). The generation of mice lacking all four CRDs (p75 NTRExonIVϪ/Ϫ ) has been described before (53). All in vivo experiments were approved by the local animal care committee and conducted in accordance with French law.…”

Section: Methodsmentioning

confidence: 99%

“…Whereas neurotrophins bind to the second to fourth CRDs (2,21), we have previously shown that RVG binding occurs on the first CRD without competition for the neurotrophin binding site (30) Although RVG binds to p75 NTR , the role of this receptor for neuronal infection has been questioned, because RV infects and kills mutant mice lacking exon III of the p75 NTR gene (25). However, the significance of this finding is unclear, because these mice express the short splice variant of p75 NTR that contains CRD1 (53), which we have shown to be sufficient for RVG binding (30). Therefore, we revisited the question of the relative importance of p75 NTR for RV infection of primary neurons of the peripheral nervous system.…”

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confidence: 99%

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The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection

Tuffereau

Schmidt

Langevin

et al. 2007

J Virol

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Rabies virus glycoprotein (RVG) is known to be the only factor that mediates rabies infection. The neurotrophin receptor (p75 NTR ), through its cysteine-rich domain 1, is a specific receptor for RVG and neutralizes virus infectivity, but its role in virus infection has remained obscure. We used adult mouse dorsal root ganglion (DRG) neurons as a model to study the role of p75 NTR in RV infection of primary neurons. We show that RV infects around 20% of DRG neurons, of which more than 80% are p75 NTR positive, have large diameters, and are capsaicin insensitive. Surprisingly, RV binding and infection are absent in about half of the p75 NTRexpressing DRG neurons which have small diameters and are often capsaicin sensitive. This indicates that p75 NTR is not sufficient to mediate RV interaction in sensory neurons. The rate and specificity of neural infection are unchanged in RV-infected p75 NTRExonIV؊/؊ mice that lack all extracellular receptor domains and in wild-type mice infected with two independent RV mutants that lack p75 NTR binding. Accordingly, the mortality rate is unchanged in the absence of RV-p75 NTR interaction. We conclude that although p75 NTR is a receptor for soluble RVG in transfected cells of heterologous expression systems, an RVG-p75 NTR interaction is not necessary for RV infection of primary neurons. This means that other receptors are required to mediate RV infection in vivo and in vitro.Rabies causes severe progressive encephalitis, myelitis, and paralysis and affects more than 50,000 people worldwide each year (59). After onset of symptoms, the infection progresses relentlessly, and there is only one documented case of a nonvaccinated human patient who survived the disease (56). Rabies virus (RV) belongs to the genus Lyssavirus in the family Rhabdoviridae and is a simple, enveloped, nonsegmented, negative-strand RNA virus that encodes only five proteins (44). The glycoprotein (G) is known to be the only protein component of the viral envelope that mediates viral entry into host cells (44).RV is highly neurotropic, and after inoculation it is retrogradely transported by peripheral neurons before being passed on to second and higher-order neurons without being taken up by glia. It is this unique property of the virus that makes it a useful transsynaptic neuronal tracer over many synapses (28,52), which is dependent on RVG (17).Although several receptors have been suggested to be responsible for RV infection, none has been conclusively identified. In previous studies we adopted an expression cloning strategy using a soluble form of RVG as a ligand. That work identified the neurotrophin receptor p75 NTR as a unique interacting receptor (50). We have also shown that the glycoprotein from another lyssavirus genotype (EBL2) is also able to interact with p75 NTR (51). p75 NTR belongs to the tumor necrosis factor receptor family (11,14) and is the common receptor for all known mature neurotrophins as well immature proneurotrophins (35). In addition, several other ligands implicated in the patholo...

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection

Tuffereau

Schmidt

Langevin

et al. 2007

J Virol

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“…The p75 À/À mice employed here have a homozygous deletion in the third exon of the p75 gene (Lee et al, 1992), which eliminates the full-length p75 receptor but not the short isoform (von Schack et al, 2001). The short isoform does not bind neurotrophins and therefore cannot mediate the functions of these factors.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

Mice lacking the p75 receptor fail to acquire a normal complement of taste buds and geniculate ganglion neurons by adulthood

Krimm

2006

Anat. Rec.

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Brain-derived neurotrophic factor and neurotrophin-4 are required for normal taste bud development. Although these neurotrophins normally function via the tyrosine kinase receptor, trkB, they also bind to the panneurotrophin receptor, p75. The goal of the present study was to determine whether the p75 receptor is required for the development or maintenance of a full complement of adult taste buds. Mice with p75 null mutations lose 34% of their circumvallate taste buds, 36% of their fungiform papillae, and 26% of their fungiform taste buds by adulthood. The reduction of taste buds in the adult circumvallate papilla was similar to that observed previously at postnatal day 7 (Fan et al. Brain Res Dev Brain Res 2004;150:23-39). Taken together, these findings indicate that the p75 receptor is critical for the development of a full complement of taste buds, but is not required for maintenance of circumvallate taste buds in adulthood. Immunolabeling for p75 was not observed in taste buds, indicating that p75 signaling influences taste bud number indirectly. Geniculate ganglion neurons, which provides innervation to fungiform taste buds, express the p75 receptor. Mice with p75 null mutations also have fewer neurons in the geniculate ganglion. Together, these results suggest that the p75 receptor is important for the survival of geniculate neurons and geniculate neuron survival is required for the development of a full complement of taste buds by adulthood.

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p75^NTR in the spleen: Age‐dependent changes, effect of NGF and 4‐methylcatechol treatment, and structural changes in p75^NTR‐deficient mice

et al. 2003

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In addition to their well-known actions within the nervous system, neurotrophins and their receptors are involved in immune system functioning, as demonstrated by their wide distribution in lymphoid tissues and their in vitro actions on immunocompetent cells. Nevertheless, the in vivo roles of neurotrophin-receptor systems in lymphoid tissues, as well as the scope of their influence throughout development and adulthood, are yet to be clarified. In the present study, we used combined morphological and immunohistochemical techniques to investigate the presence and cellular localization of p75 NTR , the pan-neurotrophin receptor protein, in rat spleen from newborns to aging individuals, and the structural and innervation changes in the spleens of p75 NTR -deficient mice. In rats, p75 NTR was expressed by splenic nerve fibers and dendritic cells in an age-regulated fashion, with maximal expression detected at 2 weeks. Consistently, the spleens of newborn mice lacking this receptor protein showed no signs of ingrowing sympathetic fibers, along with an absence of defined white pulp areas. The present findings suggest a prolonged role of p75 NTR in the physiology of the spleen; at least during the embryonic development period, the receptor may be critical for correct innervation and compartmentalization processes to occur. Anat Rec Part A 270A: 117-128, 2003.

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Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system

Cited by 235 publications

References 10 publications

The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection

The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection

Mice lacking the p75 receptor fail to acquire a normal complement of taste buds and geniculate ganglion neurons by adulthood

p75^NTR in the spleen: Age‐dependent changes, effect of NGF and 4‐methylcatechol treatment, and structural changes in p75^NTR‐deficient mice

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Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system

Cited by 235 publications

References 10 publications

The Rabies Virus Glycoprotein Receptor p75 NTR Is Not Essential for Rabies Virus Infection

The Rabies Virus Glycoprotein Receptor p75 NTR Is Not Essential for Rabies Virus Infection

Mice lacking the p75 receptor fail to acquire a normal complement of taste buds and geniculate ganglion neurons by adulthood

p75NTR in the spleen: Age‐dependent changes, effect of NGF and 4‐methylcatechol treatment, and structural changes in p75NTR‐deficient mice

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The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection

The Rabies Virus Glycoprotein Receptor p75 ^NTR Is Not Essential for Rabies Virus Infection

p75^NTR in the spleen: Age‐dependent changes, effect of NGF and 4‐methylcatechol treatment, and structural changes in p75^NTR‐deficient mice