Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system

Lee, Kuo‐Fen; Li, En; Huber, Lysiane; Landis, Story C.; Sharpe, Arlene H.; Chao, Moses V.; Jaenisch, Rudolf

doi:10.1016/0092-8674(92)90286-l

Cited by 921 publications

(717 citation statements)

References 66 publications

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“…The same was true for plasma FL, ICD and ECD signals (not shown). Since p75NTR expression plays a major role in the function of sensory and sympathetic neurons in animal models [12,13], we further studied associations with small fibre disease and different aspects of HRV as a marker of CAN. The signals for type 2 diabetic patients affected by sensory deficits (i.e.…”

Section: Resultsmentioning

confidence: 99%

Levels of three distinct p75 neurotrophin receptor forms found in human plasma are altered in type 2 diabetic patients

et al. 2007

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Aims/hypothesis The p75 neurotrophin receptor (p75NTR) has been shown to appear in the plasma of diabetic rats, possibly indicating diabetic neuropathy. The aim of this study was to use a semi-quantitative assay for human plasma p75NTR to investigate whether this receptor is a marker of peripheral diabetic neuropathy (DPN) and autonomic cardiovascular neuropathy (CAN) in type 2 diabetic patients. Subjects and methods Eighty type 2 diabetic patients and 25 controls without diabetes were analysed for p75NTR immunoreactivity by western blot analysis. DPN was assessed using the Neuropathy Disability Score (NDS). Cardiovascular autonomic function was detected using a standardised analysis of heart rate variability. Results Three distinct p75NTR signals were detectable in human plasma at ∼75, ∼51 and ∼24 kDa, representing the full length receptor (FL) and its intracellular domain (ICD) and extracellular domain (ECD), respectively. Levels of total plasma p75NTR immunoreactivity in patients with type 2 diabetes were similar to those in controls. Type 2 diabetic patients had significantly higher plasma levels of ICD and lower levels of ECD. However, there were no correlations of total p75NTR immunoreactivity or ECD or ICD immunoreactivity with NDS or aspects of CAN. Conclusions/interpretation Levels of the ECD of p75NTR are reduced and levels of the ICD are increased in the plasma of type 2 diabetic patients. None of the p75NTR subunits identified in human plasma seem to be a marker of peripheral or autonomic neuronal function in patients with type 2 diabetes.

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Section: Resultsmentioning

confidence: 99%

Levels of three distinct p75 neurotrophin receptor forms found in human plasma are altered in type 2 diabetic patients

et al. 2007

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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 p75 (p75 À/À ) have sensory neuron and receptor deficits and develop periodic lesions on their footpads (Lee et al, 1992). A specific receptor complex, comprised of specialized p75 receptor expressing cells of the epidermis known as Merkel cells (English et al, 1994;Szeder et al, 2003;Sieber-Blum et al, 2004) and slowly adapting type 1 (SA1) mechanosensory neurons, requires the p75 receptor for its maintenance during late postnatal development (Fundin et al, 1997;Stucky and Koltzenburg, 1997;Rice et al, 1998;Kinkelin et al, 1999).…”

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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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“…Some reports indicate that p75 NTR collaborates with TrkA in the formation of high-a nity binding sites and in NGF signal transduction (Hempstead et al, 1991;Barker and Shooter, 1994;Hantzopoulos et al, 1994;Verdi et al, 1994), whereas others suggest that TrkA alone may be su cient (Jing et al, 1992). From recent studies, on p75 NTR knockout mice, it appears that p75 NTR may increase neuronal sensitivity to NGF during critical developmental periods and modulate signal transduction by TrkA (Lee et al, 1992(Lee et al, , 1994Davies et al, 1993). On the other hand, Rabizadeh et al (1993) reported that p75 NTR expression in immortalized neural cells induces apoptosis after serum withdrawal.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by p75 neurotrophin receptor in human neuroblastoma cells

et al. 1997

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The low-a nity nerve growth factor receptor p75 NTR belongs to a membrane receptor superfamily whose members, in certain cell types, are able to transduce an apoptotic signal. To investigate the e ect of p75 NTR expression in neuroblastoma cells, we transfected the p75 NTR cDNA into SK-N-BE cells, a neuroblastoma cell line that lacks expression of both p75 NTR and TrkA. Cell clones expressing elevated levels of p75 NTR showed a high degree of cell death by apoptosis, even in serumsupplemented medium. Moreover, the level of apoptosis correlated directly with the expression level of the receptor, indicating that p75 NTR could activate the cell death program by itself. Clones expressing p75 NTR showed a dramatic increase of cell death when switched into serum-free medium; these cultures rapidly extinguished. This apoptotic e ect was greatly inhibited by NGF treatment. Our results support the hypothesis that p75 NTR , when it is not bound by NGF, may play a role in neuronal selection during embryonic development and suggest that neuroblastomas may arise from immature neuroblasts that escape programmed cell death. Therefore, the loss of p75 NTR expression in developing neural crest cells might be a primary event in the genesis of neuroblastoma.

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Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system

Cited by 921 publications

References 66 publications

Levels of three distinct p75 neurotrophin receptor forms found in human plasma are altered in type 2 diabetic patients

Levels of three distinct p75 neurotrophin receptor forms found in human plasma are altered in type 2 diabetic patients

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

Induction of apoptosis by p75 neurotrophin receptor in human neuroblastoma cells

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