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Volume 17, Number 11,
Issue of June 1, 1997
pp. 4398-4405
Copyright ©1997 Society for Neuroscience
The Low-Affinity Neurotrophin Receptor p75 Regulates the Function
But Not the Selective Survival of Specific Subpopulations of Sensory
Neurons
Cheryl L. Stucky and
Martin Koltzenburg
Department of Neurology, University of Würzburg, D-97080
Würzburg, Germany
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Mice with a targeted deletion of the low-affinity neurotrophin
receptor p75 (p75 /) exhibit a 50% loss of large- and
small-diameter sensory neurons in the dorsal root ganglion. Using
neurophysiological recording techniques, we now show that p75 is not
required for the survival of specific, functionally defined
subpopulations of sensory neurons. Rather, p75/ mice exhibit losses
of neurons that subserve nociceptive as well as non-nociceptive
functions. The receptive properties of large myelinated afferent fibers
were normal in p75/ mice. However, the receptive properties of
subpopulations of afferent fibers with thin myelinated or unmyelinated
axons were strikingly impaired in mice lacking p75. Furthermore, the presence of p75 is required for normal mechanotransduction in C fibers
and D-hair receptors and normal heat sensitivity in A-fiber nociceptors.
Key words:
NGF;
BDNF;
NT-3;
NT-4;
nociceptor;
dorsal root ganglion;
apoptosis;
mechanosensation;
electrophysiology
INTRODUCTION
Neurotrophins play a critical role in the
differentiation, development, and survival of sensory neurons. The
biological effects of neurotrophins are mediated by two distinct
classes of receptors. High-affinity binding of neurotrophins is
mediated by the tyrosine kinase (trk) family of receptors, in which
each neurotrophin selectively binds to a specific trk receptor
(Barbacid, 1994 ). All of the neurotrophins, however, also bind with low
affinity to the non-trk, transmembrane protein p75 (Radeke et al.,
1987; Rodríguez Tébar et al., 1990, 1992;
Hallböök et al., 1991). Trk receptors are expressed on
distinct populations of sensory neurons, because trkA is expressed
predominantly on small-diameter neurons, whereas trkC is localized to
large-diameter neurons (Mu et al., 1993; McMahon et al., 1994; Wright
and Snider, 1995). The p75 receptor, in contrast, has a much more
widespread distribution, because ~50% of all sensory neurons of
different cell sizes express p75 mRNA (Carroll et al., 1992;
Schecterson and Bothwell, 1992; Wright and Snider, 1995). Studies using
transgenic mice that have deletions for specific neurotrophins or
specific trk receptors indicate that the survival of functionally
distinct subpopulations of peripheral sensory neurons depends on
specific neurotrophins. For example, NGF and its high-affinity trkA
receptor are required for the survival of nociceptive sensory neurons
(Crowley et al., 1994; Smeyne et al., 1994), whereas NT-3 and trkC are
required for the survival of non-nociceptive mechanoreceptors (Ernfors
et al., 1994; Fariñas et al., 1994; Klein et al., 1994;
Airaksinen et al., 1996).
Little is known about the specificity of p75 in regulating the survival
and function of classes of sensory neurons. Given that all of the
neurotrophins bind p75 and given the widespread distribution of p75
among sensory neurons, an important question is whether p75 affects the
survival and function of all subtypes of sensory neurons equally or
whether it regulates specific subpopulations. Morphological studies
show that transgenic mice that lack p75 (p75/) have macroscopically
smaller dorsal root ganglia (Lee et al., 1992; Bergmann et al., 1997),
and unbiased stereological counting methods have determined that there
is a 50% loss in the total number of neurons in the dorsal root
ganglia of p75/ mice, affecting both large- and small-diameter
neurons (M. Dreetz, T. Tandrup, M. Koltzenburg, and J. Jakobsen,
unpublished observations) (see also Curtis et al., 1995; Diamond et
al., 1995). Immunohistochemical studies indicate that p75/ mice
display reduced density of cutaneous innervation by both nociceptive
and non-nociceptive sensory fibers (Lee et al., 1992; Bergmann et al.,
1997). In agreement, behavioral studies show that p75/ mice exhibit
decreased responsiveness to noxious thermal and mechanical stimuli (Lee
et al., 1992; Bergmann et al., 1997), suggesting that nociceptive
sensory neurons may be lost or functionally impaired. On the other
hand, sensory-motor deficits in p75/ mice indicate that the
survival of some non-nociceptive, myelinated mechanoreceptors may also
be compromised (Lee et al., 1995). However, p75/ mice exhibit no
selective loss of subpopulations of dorsal root ganglion neurons that
can be recognized by immunohistochemical staining for trkA, calcitonin
gene-related peptide (CGRP), the lectin IB4, or the neurofilament
antibody RT97 (Bergmann et al., 1997).
Thus, neither behavioral nor histological techniques have unequivocally
revealed whether p75 is required for the survival or function of
specific populations of sensory neurons. Here, we have used the only
technique currently available that permits direct analysis of the
prevalence and function of defined populations of sensory neurons. We
used standard electrophysiological techniques to analyze single
cutaneous sensory neurons and their response properties to natural
stimuli.
MATERIALS AND METHODS
Animals. Breeding pairs of homozygous transgenic mice
lacking p75 (p75/) (Lee et al., 1992) were obtained from Jackson
Laboratories (Bar Harbor, ME). Balb/c mice, which are part of the
genetic background of p75/ mice, were used as the p75+/+ control
and were obtained from Charles River Wiga, Sulzfeld, Germany. For both
groups, adult mice of both sexes were used, and age of mice ranged from
8 to 50 weeks and body weight ranged from 14 to 34 gm.
Neurophysiological recordings. This study was performed
using the in vitro skin-nerve preparation described
previously (Airaksinen et al., 1996). Briefly, the hairy skin of the
hindlimb was dissected together with the sural nerve, placed corium
side up in an organ bath, and superfused with oxygen-saturated,
synthetic interstitial fluid containing (in mM): 123 NaCl,
3.5 KCL, 0.7 MgSO4, 1.7 NaH2PO4, 2.0 CaCl2, 9.5 sodium gluconate, 5.5 glucose, 7.5 sucrose,
and 10 HEPES, pH of 7.45 ± 0.05, at a temperature of 32° ± 0.5°C (Fig. 1A). Single afferent
fibers were recorded extracellularly from the desheathed nerve using
gold wire electrodes. Using a low-noise differential amplifier, action
potentials were acquired on a PC and later analyzed with a custom-made
template-matching program (Forster and Handwerker, 1990). Units were
first identified by manual probing with a blunt glass rod. The
conduction velocity of each unit was determined by stimulating the
receptive field electrically with supramaximal square wave pulses of
0.1-1.0 msec duration using a Teflon-coated steel electrode (1-5 M
impedance, 300 µm shaft diameter, 5-10 µm uninsulated tip
diameter). Units conducting faster than 10 m/sec were considered to be
large myelinated (A ) fibers, units conducting slower than 1.2 m/sec
were unmyelinated C fibers, and units conducting between 1.2 and 10 m/sec were thin myelinated (A ) fibers (Airaksinen et al., 1996) (M. Koltzenburg, C. L. Stucky, and G. R. Lewin, unpublished results). For
A and A fibers, the identity of the electrically and mechanically
evoked action potentials was determined to be the same if the shape of the respective action potentials was identical. The identity of electrically and naturally evoked activity in C fibers was verified by
a standard marking procedure (Fig. 1B). Mechanical
sensitivity was determined using calibrated von Frey filaments (0.8 mm
tip diameter, 1-362 mN range of force) and sustained force stimuli (200 msec rise time, 10 sec duration of force plateau) applied by a
computer-driven, feedback-controlled stimulator (5-300 mN range of
force). Data were analyzed for 11 sec beginning with the onset of the
probe. A linear heat ramp (32°-47°C in 15 sec) was applied by a
feedback controlled lamp focused through the translucent bottom of the
organ bath onto the epidermal side of the skin, and temperature was
measured at the corium side by a thermocouple inserted into the skin.
Cold stimuli were given by isolating the receptive field with a metal
ring and applying a bolus injection of ice-cold synthetic interstitial
fluid for 5 sec, resulting in a peak temperature of 4°-8°C. Care
was taken to avoid mechanical stimulation during the thermal stimuli. A fiber was considered to respond to heat or cold if three or more action
potentials were evoked during the stimulation.
Fig. 1.
A, In vitro
skin-nerve preparation. B, Electrical stimulation
procedure used to "mark" C fibers. C fibers have a stable latency after supramaximal electrical stimulation (3 sec interstimulus interval) of the receptive field (traces 1-2). However,
after adequate activation of the fiber with a mechanical stimulus
(trace 3, mech. stim.), there is a
typical shift in the latency of the electrically evoked response that
recovers gradually (traces 4-7). The shift in
latency and recovery indicates that both the electrically and the
mechanically evoked action potentials were evoked from the same
unit.
[View Larger Version of this Image (30K GIF file)]
RESULTS
We recorded from 230 cutaneous afferent fibers in the sural nerve
which innervates the lateral part of the hairy skin of the hindpaw. Of
these fibers, 130 were studied in p75/ mice (n = 27), and 100 were studied in p75+/+ mice (n = 17) (Fig.
1A). Myelinated fibers were classified as described
previously into four subpopulations based on their conduction velocity
and adaptation properties to constant force stimuli (Airaksinen et al.,
1996). All large myelinated fibers (A) had low mechanical thresholds
and were classified as either slowly adapting (SA) or
rapidly adapting (RA) mechanoreceptors (Fig.
2A). Thin myelinated fibers (A)
were classified as either high-threshold A-mechanonociceptors
(AM) or sensitive D-hair receptors (Fig.
2B). Here, we have also studied unmyelinated fibers
in mice for the first time (Fig. 1B). As shown
previously in the rat (Kress et al., 1992), unmyelinated C fibers were
tested for their response properties to mechanical stimuli and then
classified further by their responsiveness to noxious thermal stimuli
(Fig. 2C).
Fig. 2.
Representative examples of response properties of
cutaneous afferent fibers. A, Among the A
fibers, SA mechanoreceptors fire tonically throughout a constant
low-intensity force stimulus, whereas RA fibers fire only at the on-
and offset of the stimulus. Histograms (bin width = 1 sec) indicate impulses/sec during a sustained mechanical stimulus.
B, Among A fibers, A-fiber nociceptors require
high-intensity mechanical stimuli for activation and fire tonically
throughout the stimulus. In contrast, D-hair receptors have very low
thresholds for activation (<1.0 mN) and fire at high frequencies at
the on- and offset of the stimulus. C, Representative examples of responses of a C fiber to mechanical, heat, and cold stimuli are illustrated. Response is plotted as instantaneous frequency, where each dot represents one action
potential.
[View Larger Version of this Image (19K GIF file)]
All types of functionally defined cutaneous sensory neurons present in
p75+/+ mice also were found in p75/ mice, indicating that there is
no complete loss of any functionally defined population of sensory
neurons in p75/ mice. The stimulus-response functions of the
sensory fibers in the inbred wild-type mice used here were not
different from those in another outbred wild-type strain (Airaksinen et
al., 1996). This indicates that there is little variability in the
electrophysiological parameters of afferent fibers in different strains
of wild-type mice.
Low-threshold A mechanoreceptors are normal in
p75/ mice
The prevalence of both low-threshold SA and RA mechanoreceptors in
p75/ mice was normal. Thirty-eight percent of A fibers in
p75/ mice were SA, compared with 41% in p75+/+ mice. The remainder
of the A fibers in both groups were RA fibers (Fig. 3). Furthermore, the mechanical sensitivity of both SA
and RA mechanoreceptors was unaltered in p75/ mice. First, there
were no differences in the von Frey thresholds of either SA or RA
mechanoreceptors in p75/ mice, compared with wild-type mice (Table
1). Second, the stimulus-response functions, which
correlate force to discharge frequency, were unaltered for both SA and
RA fibers in p75/ mice (Fig.
4A,B). SA fibers in
both p75/ and p75+/+ mice encoded the stimulus intensity in the
lower range of intensities used (5-20 mN) and saturated at higher
stimulus intensities. RA fibers in both groups exhibited a discharge at
all stimulus intensities and responded only at the on- and offset of
the stimulus.
Fig. 3.
Prevalence of functionally defined sensory
receptors among A and A fibers. The asterisk
indicates that the number of fibers in p75/ mice is significantly
different from that for p75+/+ mice; p < 0.05,  2 test.
[View Larger Version of this Image (17K GIF file)]
Fig. 4.
Stimulus-response functions of cutaneous fibers
to constant force stimuli. There were no statistically significant
differences in the mechanical stimulus-response functions of SA
(F(1,139) = 0.44, p > 0.5), RA (F(1,158) = 2.24, p > 0.1), or AM
(F(1,458) = 2.41, p > 0.1) fibers between p75/ and p75+/+ mice. However, the
stimulus-response functions for D-hair receptors
(F(1,208) = 30, p < 0.001) and C fibers (F(1,277) = 16.5, p < 0.001) were significantly reduced in p75/
mice, compared with p75+/+ mice. Values indicate mean frequency ± SEM of action potentials per second for all fibers. Statistical
differences were tested using ANOVA.
[View Larger Version of this Image (21K GIF file)]
Nociceptors in p75/ mice are reduced in number and impaired
in function
In contrast to low-threshold A mechanoreceptors, which were
unaltered in p75/ mice, nociceptive sensory neurons in p75/ mice displayed deficits in several aspects. First, the prevalence of AM
nociceptors was reduced significantly from 68% in p75+/+ mice to 42%
in p75/ mice (p < 0.05, 2 test) (Fig. 3). Second, whereas the mechanical
sensitivity of the remaining AM nociceptors in p75/ mice was normal
(Table 1, Fig. 4C), the heat sensitivity of these
nociceptors was reduced significantly. None of the AM fibers in
p75/ mice responded to heat, in contrast to 26% of AM nociceptors
in p75+/+ mice that were heat-sensitive (p < 0.05, 2 test) (Table 2). However, there
was no difference in the sensitivity of AM fibers to cold stimuli in
p75/ and p75+/+ mice (Table 2).
There was no significant difference in the proportion of thermally
sensitive unmyelinated fibers, because 64% of C fibers in p75/
mice responded to heat, compared with 41% in p75+/+ animals
(p > 0.1, 2 test) (Table 2).
There was a marginally significant difference in the mean conduction
velocity of C fibers between p75/ mice (0.58 ± 0.03 m/sec;
n = 32) and p75+/+ mice (0.69 ± 0.05 m/sec; n = 23). However, this small difference would not
account for the slightly but not significantly increased proportion of
C fibers in p75/ mice that responded to heat, because the response
properties of C fibers do not correlate with conduction velocities
(Kress et al., 1992). There also was no difference between the two
groups of mice in the heat threshold or average number of action
potentials evoked by the standard heat stimulus
(p > 0.05, Student's t-test) (Table
2). Furthermore, there was no difference in the proportion of C fibers
that responded to cold stimuli (Table 2). However, the mechanical
sensitivity of unmyelinated C fibers in p75/ mice was reduced
significantly (Fig. 4E). At all stimulus intensities tested, C fibers in p75/ mice discharged ~50% fewer action
potentials to mechanical stimuli than C fibers in p75+/+ mice (Fig.
4E). Whereas C fibers in p75+/+ mice encoded the
strength of the mechanical stimulus throughout the range of stimuli, C
fibers in p75/ mice saturated at much lower forces (100 mN). For an
individual stimulus, the reduced mechanical responsiveness of C fibers
was present for the duration of the sustained stimulus (Fig.
5A).
Fig. 5.
Mean discharge frequency per second during
supramaximal mechanical stimuli for C fibers and D-hair receptors.
A, C fibers in p75/ mice exhibited reduced frequency
of firing throughout a supramaximal stimulus, compared with p75+/+
mice. Bars (bin width = 1 sec) indicate the mean
impulses/sec evoked in response to a 200 mN sustained stimulus for all
C fibers tested. B, D-hair receptors in p75/ mice
exhibited reduced frequency of firing, primarily during the first 2 sec
after onset of the stimulus. Bars indicate the mean
impulses/sec evoked in response to a 100 mN sustained stimulus for all
D-hair receptors tested.
[View Larger Version of this Image (14K GIF file)]
Non-nociceptive D-hair receptors in p75/ mice have reduced
mechanical sensitivity
In contrast to low-threshold SA and RA mechanoreceptors, which
were normal in both their prevalence and their responsiveness to
mechanical stimuli, low-threshold D-hair receptors in p75/ mice
showed significantly reduced responsiveness to mechanical stimuli at
all stimulus intensities tested (Fig. 4D). The
reduced frequency of firing occurred primarily within the first 2 sec after onset of the stimulus, the time when peak firing of D-hair receptors occurs with constant force mechanical stimuli (Fig. 5B).
DISCUSSION
Adult mice that lack the low-affinity neurotrophin
receptor have all types of functionally defined cutaneous primary
afferent neurons found in wild-type mice. In spite of the 50% loss in
total sensory neurons in p75/ mice, no functionally defined subtype of sensory neuron is preferentially lost. Furthermore, we show that the
specific deficits in populations of sensory neurons in p75/ mice
are losses in function. C-fiber nociceptors and low-threshold D-hair
receptors have reduced mechanical responsiveness, and AM nociceptors
are completely heat-insensitive. Thus, p75 is not required for the
survival of a specific, functionally defined subpopulation of sensory
neurons; however, p75 is important for the mechanical responsiveness of
C fibers and D-hair receptors and the heat sensitivity of A-fiber
nociceptors.
Nociceptive and non-nociceptive sensory neurons are lost in
p75/ mice
Unbiased stereological counting methods have shown that p75/
mice exhibit a 50% loss in the total number of sensory neurons in the
dorsal root ganglion, including both large- and small-diameter neurons
(M. Dreetz, T. Tandrup, M. Koltzenburg, and J. Jakobsen, unpublished
observations). Furthermore, immunohistochemical studies show that these
mice have markedly reduced innervation of the skin by both nociceptive
and non-nociceptive sensory fibers (Bergmann et al., 1997). Because
~50% of neurons in the dorsal root ganglion express the p75 receptor
(Carroll et al., 1992; Schecterson and Bothwell, 1992; Wright and
Snider, 1995), one obvious possibility is that all p75-expressing
neurons are lost in p75/ mice. However, histological studies
suggest that this is not the case. In rat, virtually all
trkA-expressing sensory neurons and all CGRP-containing neurons also
express p75, whereas IB4-expressing neurons do not (Wright and Snider,
1995). Yet there is no change in the percentages of trkA-positive,
CGRP-positive, or IB4-positive neurons in p75/ mice (Bergmann et
al., 1997). Although we cannot completely exclude the possibility that
there may be independent changes in the distribution of these markers
during development, these data suggest that both p75-positive and
p75-negative neurons are lost equally.
Another possible explanation for the 50% cell loss in p75/ mice is
that only nociceptive neurons are lost. The survival of nociceptors
depends on the presence of NGF and its high-affinity receptor trkA
(Ruit et al., 1992; Crowley et al., 1994; Smeyne et al., 1994). Sensory
neurons cultured from p75/ mice show decreased NGF-dependent
survival (Lee et al., 1994). Furthermore, p75/ mice display reduced
behavioral responses to noxious thermal and mechanical stimuli (Lee et
al., 1992; Bergmann et al., 1997). However, two pieces of evidence
indicate that preferential loss of nociceptors does not account for the
cell death. First, in p75/ mice, there is no selective loss of
trkA-, CGRP-, or IB4-expressing sensory neurons, which are likely to be
nociceptors (McMahon et al., 1994; Averill et al., 1995; Wright and
Snider, 1995; Bergmann et al., 1997). Second, although we observed a
slight reduction in the prevalence of AM nociceptors among the thin
myelinated fiber population, this cannot account for the 50% loss of
cells in the dorsal root ganglion, because all thin myelinated fibers together make up only 10% of the total fibers that innervate the skin
(Albers et al., 1996).
Given that p75/ mice do not exhibit a selective loss of
nociceptors, another possibility is that a selective loss of
non-nociceptive neurons may account for the 50% cell death. We studied
three different populations of low-threshold non-nociceptive neurons,
including SA fibers, RA fibers, and D-hair receptors, and we found that no selective loss of any of these fiber types occurred in p75/ mice. We have shown in previous studies that NT-3 is crucial for the
survival of SA fibers, whereas NT-3 and NT-4 both support survival of
D-hair receptors (Airaksinen et al., 1996; Stucky et al., 1996).
Therefore, our results conclude that the p75 receptor plays no critical
role in the NT-3- or NT-4-mediated survival of SA fibers or D-hair
receptors. Together, the electrophysiological and histological data
show that both nociceptive and non-nociceptive sensory neurons are lost
in p75/ mice. One mechanism by which this nonselective loss in
sensory neurons may occur is if neurons are lost before they are
committed to their functional phenotypes.
Specific functionally defined subpopulations of sensory neurons in
p75/ mice have losses in function
The data presented in this paper demonstrate that although no
selective losses of specific populations of sensory neurons occur in
p75/ mice, important functional changes occur in specific subtypes
of sensory neurons. This could mean that p75 plays a key role in
mediating the function of sensory neurons after they have
differentiated into functional phenotypes. Large myelinated low-threshold SA and RA fibers in p75/ mice were completely normal
in function. We have shown previously that BDNF is required for the
normal mechanotransduction of SA fibers (Koltzenburg et al., 1995).
Therefore, our results show that p75 is not required for the
BDNF-mediated mechanical function of SA fibers or the mechanical
function of RA fibers.
Because none of the AM fibers responded to heat in p75/ mice,
p75 is required for the expression of heat sensitivity in AM
nociceptors. The loss of heat-sensitive AM fibers could be attributable
either to the selective death of these fibers or to a phenotype switch.
Because no specific marker for heat-sensitive AM fibers is available at
this time, we cannot exclude the possibility that there may be
selective cell death of heat-sensitive AM fibers. However, we favor the
explanation that the heat-sensitive AM fibers in p75/ mice
underwent a phenotype switch, because other studies have shown that AM
nociceptors undergo a permanent phenotype switch to D-hair receptors
after postnatal treatment with antibodies that neutralizes endogenous
NGF (Ritter et al., 1991; Lewin et al., 1992). Additional evidence from
our laboratory suggests that the ligand responsible for the change in
AM fibers in p75/ mice is NGF, because NT-3, BDNF, or NT-4 are not
required for the survival or function of AM nociceptors (Koltzenburg et
al., 1995; Airaksinen et al., 1996; Stucky et al., 1996). Furthermore,
the heat sensitivity of A fibers is not a constant feature of this
subpopulation of fibers, but instead is quite variable. For example,
after inflammation of the skin, many AM fibers become heat sensitive
(Meyer and Campbell, 1981; Thalhammer and LaMotte, 1982), and NGF has
been implicated in this process. In adult animals, application of
exogenous NGF induces many AM fibers to become responsive to heat
within seconds (Rueff and Mendell, 1995; Tal et al., 1996). Conversely,
sequestration of NGF by a trkA-IgG fusion molecule prevents the
sensitization of nociceptors to heat in inflamed skin (Bennett et al.,
1996). Because p75 has been shown to enhance the affinity of trkA for NGF (Hempstead et al., 1991), p75 may regulate the NGF-dependent postnatal phenotype of AM fibers by enhancing NGF signaling.
The mechanical transduction in two populations of neurons was impaired
in p75/ mice. C-fiber nociceptors, which respond tonically to
high-threshold stimuli, and non-nociceptive D-hair receptors, which
respond only to the on- or offset of a stimulus, both exhibited reduced
frequency of firing to mechanical stimuli. Thus, p75 regulates normal
mechanotransduction in both nociceptive and non-nociceptive neurons as
well as in neurons with both slowly and rapidly adapting properties.
Although NGF mediates the survival (Crowley et al., 1994) and phenotype
(Lewin and Mendell, 1994) of C fibers, the effect of p75 on the
mechanical function of C fibers is not likely mediated by NGF. First,
sequestration of endogenous NGF in neonatal rats results in C fibers
that are very sensitive to mechanical stimuli (Lewin and Mendell, 1994)
and, second, sequestration of NGF in adult animals leaves mechanical responsiveness unchanged (Koltzenburg et al., 1996). Furthermore, sequestration of endogenous NGF in either neonatal or adult rats results in C fibers with significantly reduced heat sensitivity (Lewin
and Mendell, 1994; Koltzenburg et al., 1996). However, C fibers in
p75/ mice had normal heat sensitivity. Thus, p75 regulates the
mechanical sensitivity of C fibers through an NGF-independent mechanism, and p75 is not involved in the regulation of the sensitivity of C fibers to heat.
It is not known which ligand(s) activates the p75 receptor to
modulate the mechanical sensitivity of D-hair receptors. The ligand is
unlikely to be NGF, BDNF, or NT-3, because D-hair receptors in animals
that lack each of these neurotrophins, respectively, are normal in
mechanical function (Ritter et al., 1991; Koltzenburg et al., 1995;
Airaksinen et al., 1996). One possibility is that the ligand is NT-4.
Retrograde transport of NT-4 in p75/ mice is reduced more severely
than is transport of the other neurotrophins (Curtis et al., 1995). In
addition, we found that in transgenic mice that lack NT-4, D-hair
receptors are almost completely absent (Stucky et al., 1996). This
could mean that NT-4 is required to mediate the survival of D-hair
receptors by binding to trk receptors, whereas the presence of p75 is
necessary to mediate NT-4-dependent function of D-hair receptors.
The cellular mechanisms underlying p75-mediated survival and function
are not yet clear. Because p75 has been proposed to be involved in
several signal transduction pathways, p75 may mediate cell survival and
function through different mechanisms. p75 has been shown to interact
directly with trk receptors by increasing the local concentration of a
neurotrophin in the vicinity of its cognate trk receptor (Barker and
Shooter, 1994), by increasing autophos-phorylation of the trk receptors
(Berg et al., 1991; Verdi et al., 1994), or by enhancing the
discrimination of the trk receptors for their preferred ligands
(Rodríguez Tébar et al., 1992; Benedetti et al., 1993).
Alternatively, p75 may signal directly, either by stimulating
production of ceramide through activation of sphingomyelin (Dobrowsky
et al., 1994, 1995) or by activating the transcription factor NF B
(Carter et al., 1996). A recent study has shown that NFB is not
active in the developing mouse until after birth, suggesting that
NFB does not play a role in developing and differentiating tissue,
but instead maintains the function of tissue once it has matured
(Schmidt-Ullrich et al., 1996). Thus, an intriguing possibility is that
the p75-NFB pathway may regulate the p75-dependent function of
sensory neurons.
Future studies are necessary to sort out the specific pathways involved
in neuronal survival and function. Studies that determine when the
p75-dependent neuronal loss occurs during embryogenesis in p75/
animals may illuminate mechanisms underlying the cell loss. Moreover,
mechanical sensitivity is not the only sensory function modulated by
p75 in unmyelinated nociceptors. A recent study has shown that the
expression of bradykinin receptors on presumptive nociceptors in
culture is mediated by a specific interaction between NGF and p75
(Petersen et al., 1996), demonstrating that p75 also modulates
chemosensitivity.
Knowledge about the role of p75 in regulating the sensitivity of
nociceptors has important clinical implications. First, because increased sensitivity of nociceptors occurs in chronic pain states (Koltzenburg, 1996), reversing the increased excitability could lead to
the development of novel analgesics. Second, the function of sensory
neurons is typically impaired in polyneuropathies. For example, in
patients with diabetic polyneuropathy, reduced levels of neurotrophins
in tissue correlate with the functional deficits (Anand, 1996). Thus,
knowledge of mechanisms that compromise neurotrophin signaling may
advance the understanding of the pathobiology and treatment of this
prevalent neurodegenerative disease.
FOOTNOTES
Received Nov. 27, 1996; revised Feb. 21, 1997; accepted March 14, 1997.
This work was supported by the Deutsche Forschungsgemeinschaft,
Sonderforschungsbereich 353.
Correspondence should be addressed to Dr. Martin Koltzenburg,
Department of Neurology, University of Würzburg,
Josef-Schneider-Strasse 11, D-97080 Würzburg,
Germany.
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