Identification of a truncated form of the nerve growth factor receptor.

DiStefano, Peter S.; Johnson, Eugene M.

doi:10.1073/pnas.85.1.270

Cited by 121 publications

(63 citation statements)

References 34 publications

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“…First, gp72CNTF-K may be cleaved from the cell surface and released in a soluble form that retains CNTF binding. A soluble form of the low-affinity subunit of the NGF receptor is secreted in urine, for example, and its amount is increased by trauma to peripheral nerves (DiSteffano and Johnson, 1988). Second, cells that express gp72CNTF-R will bind CNTF, but may not have a functional response to CNTF if the gene for the proposed tyrosine kinase subunit is not coordinately expressed.…”

Section: Discussionmentioning

confidence: 99%

Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor

1992

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Ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF) were tested for effects on sprouting by motor neurons innervating the adult mouse gluteus muscle. Factors were delivered by subcutaneous injection directly over the surface of the superior gluteus muscle once daily for 7 d and then end plates and axons were visualized by combined silver and cholinesterase staining. CNTF (500 ng daily) induced sprouting both from end plates and from the subset of nodes of Ranvier that are closest to the end plate. The effect of CNTF was potentiated twofold by coadministration of bFGF at doses of 2-20 ng daily, whereas treatment with bFGF alone failed to induce sprouting from either end plates or nodes of Ranvier. The sprouting stimulus delivered by the factors showed limited penetrance into the muscle and restricted lateral spread from the injection site.Two types of trauma induce motor neuron sprouting in muscle, partial denervation and paralysis. These induce sprouting both from end plates and from nodes of Ranvier. At least two physiological signals have been proposed to control sprouting (Brown et al., 1981). One is produced by muscle as a consequence of paralysis, and the other is produced within intramuscular nerves due to the presence of degenerating axons.The evidence that muscle is the source of the paralysis-induced signal for sprouting includes the following. First, paralysis of muscle by blockade of axonal conduction with TTX (Brown and Ironton, 1977) blockade ofACh release by botulinum toxin (Duchen, 1970) and blockade of ACh action by a-bungarotoxin (Holland and Brown, 1980) all induce sprouting from motor axon terminals. Since all of these manipulations have only one effect in common, induction of muscle paralysis, paralyzed muscle is likely to be the source of the signal for terminal sprouting. Second, the induction of sprouting by botulinum toxin can be blocked by restoring contractile activity in the paralyzed muscle through direct electrical stimulation (Brown et al., 1980a). Partial denervation also induces sprouting from undamaged motor axon terminals, and this too can be blocked by electrical stimulation (Ironton et al., 1978).The strongest stimulus for nodal sprouting, in contrast, is the presence of degenerating axons (Brown et al., 1980a). Partial denervation induces nodal sprouting from undamaged axons

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Section: Discussionmentioning

confidence: 99%

Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor

1992

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“…The p75 NTR was purified from tissue sources some years ago, antibodies were raised and a truncated form (p50), expressed particularly by Schwann cells, was found to contain a similar epitope to the mature receptor [13]. This same antibody was also used to demonstrate p75-like immunoreactivity in the urine of diabetic patients diagnosed with neuropathy [14].…”

Section: Fractionation Of Plasma Proteins By Sds-pagementioning

confidence: 99%

The p75 neurotrophin receptor appears in plasma in diabetic rats?characterisation of a potential early test for neuropathy

et al. 2004

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Aims/hypothesis. This study tested the premise that immunoreactivity representing the p75 neurotrophin receptor (p75 NTR ) appears in plasma of diabetic rats in association with the early stages of neuronal dysfunction or damage. We also examined whether treatment beneficial to neuropathy might reduce the p75 NTR immunoreactivity. Methods. Plasma proteins were fractionated by SDS-PAGE and immunoblots exposed to p75 NTR antibody, using receptor protein from cultured PC12 cells as an external standard. Rats were made diabetic with streptozotocin for various periods and exsanguinated. Plasma glucose, HbA 1 c and plasma proteins were determined. We also studied plasma samples from diabetic mice lacking the gene coding for p75 NTR , as well as the effect of sciatic nerve crush on healthy male Wistar rats. Results. Plasma p75 NTR immunoreactivity began to exceed normal levels at 8 weeks after induction of diabetes, and was significantly raised at 10 (p<0.05) and 12 weeks (p<0.001). Treatment between 8 and 12 weeks with insulin, fidarestat (an aldose reductase inhibitor), nerve growth factor and neurotrophin 3 all normalised the plasma p75 NTR immunoreactivity. Plasma from p75 NTR (−/−) mice contained no such immunoreactivity, though it was present in plasma from wild-type mice. Following nerve crush, p75 NTR immunoreactivity appeared in plasma of non-diabetic mice, indicating that this can be a result of nerve trauma. Conclusions/interpretation. These observations suggest that plasma p75 NTR immunoreactivity may serve as an early indicator of neuronal dysfunction or damage in diabetes. The time course of its appearance relates well to that of early neuropathy and its response to interventions that are neuroprotective suggests that it might mirror neurological status.Keywords Nerve growth factor · Neuropathy · Neurotrophins · p75 NTR · Plasma marker · Rats · Receptor shedding

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“…In addition, a truncated form of the low-affinity receptor is secreted into the extracellular medium of cultured Schwann cells, PC12 cells, and superior cervical ganglia neurons, as well as the plasma and urine of normal rats (13).…”

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Nerve growth factor binding domain of the nerve growth factor receptor.

Welcher

Bitler

Radeke

et al. 1991

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

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A structural analysis of the rat low-affinity nerve growth factor (NGF) receptor was undertaken to define the NGF binding domain. Mutant NGF receptor DNA constructs were expressed in mouse fibroblasts or COS cells, and the ability of the mutant receptors to bind NGF was assayed.In the first mutant, all but 16 amino acid residues of the intracellular domain of the receptor were removed. This receptor bound NGF with a Kd comparable to that of the wild-type receptor. A second mutant contained only the four cysteine-rich sequences from the extraceflular portion of the protein. This mutant was expressed in COS cells and the resultant protein was a secreted soluble form of the receptor that was able to bind NGF. Two N-terinal deletions, in which either the first cysteine-rich sequence or the first and part of the second cysteine-rich sequences were removed, bound NGF. However, a mutant lacking all four cysteine-rich sequences was unable to bind NGF. These results show that the four cysteinerich sequences of the NGF receptor contain the NGF binding domain.The role of nerve growth factor (NGF) in the development and survival of peripheral sensory and sympathetic neurons has been well characterized (1). Studies have also suggested a role for NGF in the development and maintenance of cholinergic neurons in the mammalian forebrain (2).The first step in the mechanism of action of NGF is the interaction of NGF with its specific receptor [the NGF receptor (NGFR)] on responsive cells or cell lines. There are two types or states of the NGFR as determined by binding studies (3). On sensory and sympathetic neurons, these receptors are described as high-affinity (Kd = 10 pM) and low-affinity (Kd = 1 nM) NGFRs, respectively. Although the NGFRs in PC12 cells differ less in their Kd values, they share many features of the receptors on primary neurons, including a slower rate ofdissociation of NGF from the high-compared to the low-affinity receptor (4). The biological response of NGF in neuronal cells correlates with occupancy of the high-afflinity receptor. Indirect evidence suggests that the high-affinity NGFR comprises the low-affinity receptor complexed with an additional cytoplasmic or membraneassociated protein or proteins (5,6). The low-affinity receptor has been cloned in rat (7), chicken (8), and human (9), and the three receptors share considerable homology.Recent studies have shown that Schwann cells in rat sciatic nerve express high levels of the low-affinity NGFR after nerve crush or transection (10, 11). This expression is repressed once contact is reestablished between the Schwann cells and the regenerating axons. These low-affinity receptors may bind the NGF that is synthesized by nonneuronal cells distal to a peripheral nerve injury and create a localized source of NGF on the surface of the Schwann cells over which the advancing neuronal growth cone migrates (12).In addition, a truncated form of the low-affinity receptor is secreted into the extracellular medium of cultured Schwann cells, PC12 cells, and super...

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Identification of a truncated form of the nerve growth factor receptor.

Cited by 121 publications

References 34 publications

Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor

Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor

The p75 neurotrophin receptor appears in plasma in diabetic rats?characterisation of a potential early test for neuropathy

Nerve growth factor binding domain of the nerve growth factor receptor.

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