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Volume 16, Number 19,
Issue of October 1, 1996
pp. 6107-6118
Copyright ©1996 Society for Neuroscience
Axonal Interactions Regulate Schwann Cell Apoptosis in Developing
Peripheral Nerve: Neuregulin Receptors and the Role of
Neuregulins
Judith B. Grinspan1,
Mark A. Marchionni2,
Matthew Reeves1,
Markella Coulaloglou1, and
Steven S. Scherer3
1 Division of Neurological Research, Children's
Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, 2 Cambridge NeuroScience, Cambridge, Massachusetts 02139, and 3 Department of Neurology, The University of
Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6146
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Programmed cell death during development resulting from the lack of
appropriate survival factors has been demonstrated in both neurons and
oligodendrocytes and occurs mostly in the form of apoptosis. We now
demonstrate that Schwann cells in the rat sciatic nerve undergo
apoptosis during early postnatal development and that the amount of
apoptosis is markedly increased by axotomy. The apoptotic Schwann cells
express the low-affinity nerve growth factor receptor but not
myelin-related proteins, indicating that they are in the premyelinating
state. Apoptosis resulting from normal development or from axotomy can
be inhibited markedly by exogenous neuregulin. Consistent with this,
the neuregulin receptor components erbB2 and
erbB3 are expressed and phosphorylated in developing
sciatic nerve. These data suggest that Schwann cell number in
developing peripheral nerve is regulated by apoptosis through
competition for axonally derived neuregulin.
Key words:
myelin;
axon-Schwann cell interactions;
S-100;
erbB2;
neu;
erbB3;
cell death;
glia
INTRODUCTION
In the developing CNS and peripheral nervous
system (PNS), the differentiation of neurons is accompanied by a large
amount of cell loss in the form of programmed cell death. Cells that
die from programmed cell death are most commonly eliminated by
apoptosis, a process characterized by nuclear fragmentation in an
otherwise intact cell. Initially, the chromatin condenses, the
nucleolus disintegrates, and the nucleus shrinks; eventually, the
nucleus and cytoplasm bud and separate into multiple, membrane-bound
apoptotic bodies that are phagocytosed by macrophages or surrounding
cells (Kerr et al., 1972 ; Arends et al., 1990; Sen, 1992; Wijsman et
al., 1993). These processes have been studied extensively in developing
PNS neurons, whose survival depends on trophic factors that are
provided by their targets (Purves and Lichtman, 1985; Korsching, 1993;
Snider, 1994). Neuronal cell death results from competition for limited
amounts of growth factors and may serve various purposes, such as
eliminating inappropriate connections or matching the number of neurons
to the size of their target (Cowan et al., 1984).
Schwann cells, the sole glial cell of the PNS, also die during
development. The earliest Schwann cells are known as precursors and
have been characterized extensively in vitro by Jessen and
Mirsky and their colleagues (Jessen and Mirsky, 1992; Jessen et al.,
1994; Gavrilovic et al., 1995; Stewart et al., 1995). Precursors appear
at approximately embryonic day 14 (E14), but do not express the markers
of more mature Schwann cells, S100 , O4, O1, and galactocerebroside,
which are acquired later (beginning at E17). Schwann cell precursors,
but not Schwann cells, are trophically dependent on basic fibroblast
growth factor (bFGF), insulin-like growth factor-1 (IGF-1), or
neuregulins for their survival in culture.
Neuregulins [also known as glial growth factors (GGF), neu
differentiation factor, heregulins, and ARIA] are a group of peptide
growth factors expressed by embryonic neurons (Marchionni et al., 1993)
and mesenchymal cells (Meyer and Birchmeier, 1994). The forms of
neuregulins that correspond to the GGF were identified originally as an
activity from pituitary glands that stimulated proliferation of
astrocytes and Schwann cells (Brockes et al., 1980; Lemke and Brockes,
1984; Lemke, 1990). Subsequent purification of the peptides and cloning
of the neuregulin gene demonstrated that alternative splicing of the
neuregulin gene generates multiple isoforms, including ones that are
predicted to be intracellular, transmembrane, or secreted (Marchionni
et al., 1993; Wen et al., 1994). The importance and activities of the
various isoforms have just begun to be elucidated, but the so-called
 and isoforms, created by the alternative splicing of an
epidermal growth factor-like domain, differ in their potency as
mitogens and survival factors for Schwann cell precursors (Dong et al.,
1995). The major isoform made by sensory and motor neurons has been
described recently (Ho et al., 1995), but its relative potency as
compared with the other neuregulin isoforms has yet to be established.
Motor and sensory neurons probably express and axonally transport
neuregulins beginning in early embryonic stages (Marchionni et al.,
1993; Chen et al., 1994; Corfas et al., 1995; Sandrock et al., 1995),
making it plausible that axonally derived neuregulins are continuously
available to Schwann cells from the earliest times in their
development.
In this paper, we report that Schwann cells are subjected to programmed
cell death in vivo during the first two postnatal weeks, and
axotomy greatly augments the number of apoptotic Schwann cells during
this developmental window but not in older animals. Schwann cells in
these neonatal nerves express a neuregulin receptor composed of
erbB2 (also known as c-neu) and erbB3,
both of which are phosphorylated in vivo, presumably in
response to endogenous neuregulins. Exogenous neuregulin completely
abolishes the increase in apoptotic Schwann cells induced by axotomy.
The apoptotic Schwann cells do not express myelin-related proteins but
do express the low-affinity nerve growth factor receptor (NGFR)/p75 and
erbB2. These results demonstrate that one of the ways
axon-Schwann cell interactions regulate Schwann cell number in
developing nerves is through apoptosis, and they suggest that
competition for a limited amount of axonally derived neuregulin may be
the mechanism for pruning excessive Schwann cells generated during
development.
MATERIALS AND METHODS
Surgery and injection of neuregulin. All animal
protocols were approved by the Institutional Animal Care and Use
Committee of The University of Pennsylvania. Newborn [the day of birth
is considered to be postnatal day zero (P0)] and P5 rats were
anesthetized in an ice-water bath. Using aseptic technique, the left
sciatic nerve was exposed at the sciatic notch and transected with fine
scissors. The right sciatic nerve was not lesioned and served as a
control. The skin was closed with suture, and the pups were
resuscitated by warming and then returned to their mothers. P20 and
young adult (P90) Sprague-Dawley rats were anesthetized with
pentobarbital (50 mg/kg, i.p.), and the sciatic nerve was exposed at
the sciatic notch and transected with fine scissors. In adult rats that
were allowed to survive for >4 d, permanent axotomy was accomplished
by doubly ligating nerves, transecting between the ligatures with fine
scissors, and suturing; the two nerve stumps were at least 1 cm apart.
This technique prevents axonal regeneration to the distal nerve stump
for at least 2 months. At various times after nerve injury, the animals
were killed by CO2 inhalation, the distal nerve stumps were
removed, and the most proximal 2-3 mm were trimmed off and processed
as described below. Nerves from unlesioned animals were prepared
similarly.
Two groups of experiments were carried out. (1) To establish the time
course of apoptosis after axotomy at P0, P5, and P20, animals were
killed 1, 2, 3, or 4 d postlesion. P90 animals were killed after
1, 4, 8, 12, 24, and 58 d. (2) To determine whether neuregulin
could rescue axotomized Schwann cells, a recombinant human (rh)
secreted isoform of neuregulin [rhGGF2 after the nomenclature in
Marchionni et al. (1993)] dissolved in 200 mM NaCl in 20 mM acetate buffer, pH 6.5, was injected into the left thigh
at a dose of 1.0 µg/gm body mass. The first injection was carried out
6 hr before axotomy of the left sciatic nerve, the second at the time
of axotomy, and the third and fourth, 8 and 16 hr after axotomy. The
animals were killed 24 hr after axotomy. As controls, littermates were
injected with an identical volume of the vehicle on the same schedule.
Both the left (lesioned) and right (unlesioned) nerves were removed for
analysis.
Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin
nick-end labeling (TUNEL) assay and immunohistochemistry. Nerves
were fixed overnight in 4% paraformaldehyde in 0.1 M
phosphate buffer, pH 7.4, freshly prepared from paraformaldehyde,
cryoprotected in 20% sucrose in 0.1 M phosphate buffer, pH
7.4, and embedded in OCT (Miles, Elkhart, IN). Longitudinal sections, 5 µm thick, were mounted on Superfrost (Fisher Scientific, Orangeburg,
NY) glass slides. For immunostaining, the sections were blocked for at
least 1 hr (20% fetal calf serum, 1% BSA, 0.1% Triton X-100, 0.05%
sodium azide, in PBS) and incubated 24-48 hr at 4°C with one of the
following antibodies: mouse monoclonal antibodies against the
low-affinity NGFR/p75 (Chandler et al., 1985), rat erbB2
(Oncogene Science #4, Oncogene Science, Manhasset, NY) and rabbit
polyclonal antibodies against rat S100 (EastAcres Biologicals,
Southbridge, MA), periaxin (Gillespie et al., 1994), or
erbB2 (Santa Cruz SC284, Santa Cruz Biotechnology,
Tebu,France). We also stained sections of neonatal rat sciatic nerve
with two additional monoclonal antibodies against erbB2
(Oncogene Science #2, Oncogene Science, and Cambridge Research
Biochemicals, Cheshire, UK), as well as two polyclonal rabbit antisera
against erbB2 (E19420, Transduction Labs, Lexington, KY, and
SC284, Santa Cruz Biotechnology). All of these erbB2
antibodies gave the same pattern of staining in sections of rat sciatic
nerve by immunofluorescence. Three different rabbit polyclonal antisera
against erbB3 [SC285, Santa Cruz Biotechnology; E38530,
Transduction Laboratories; and gift of Dr. Kermit Carraway (Soltoff et
al., 1994)], and a rabbit polyclonal antisera against erbB4
antisera (Santa Cruz SC283) did not label sections of neonatal rat
sciatic nerve. After they were incubated with the primary antibodies,
the sections were washed and then incubated with the appropriate
fluorescein-conjugated goat anti-rabbit or anti-mouse secondary
antibody (Cappel Division of Organon-Teknica, Malvern, PA).
After the immunohistochemistry, we used a modification of the TUNEL
assay (Gavrieli et al., 1992). Sections were incubated in 0.5% Triton
X-100 for 15 min at room temperature and preequilibrated in TdT buffer
(30 mM Trizma base, pH 7.2, 140 mM sodium
cacodylate, 1 mM cobalt chloride) before the addition of
TdT (18 U/coverslip) and biotinylated dUTP. The sections were incubated
at 37°C for 60 min, and then the reaction was terminated by
incubating in buffer (300 mM sodium chloride, 30 mM sodium citrate) for 15 min at room temperature. The
sections were rinsed in PBS containing 2% BSA for 10 min, incubated in
strepavidin rhodamine diluted 1:50 in PBS for 30 min at room
temperature followed by rinsing in PBS. 4,6-Diamidino-2-phenylidole
(DAPI) was applied to the sections for 5 min at room temperature to
counterstain the nuclei. The sections were washed in PBS, mounted in
Vectashield (Vector Labs, Burlingame, CA), coverslipped, and examined
with a Leica TCS confocal microscopy system.
To quantify Schwann cell apoptosis, two or more longitudinal sections
of sciatic nerve were mounted on a slide. The slide was oriented so
that the top of each section was at the top of the microscope field.
Using the 100× lens, we counted all of the nuclei (using DAPI
fluorescence) in that field, as well as all of the TUNEL-positive cells
(using rhodamine fluorescence). Each field was counted at least twice
and a third or even a fourth time if the numbers did not agree
sufficiently, and an average was determined. Then the stage was moved
so that the very bottom of the first field was now at the very top of
the second, and the counting process was repeated. In this way, three
to five fields were counted from the ``top'' to the ``bottom'' of
each section. Every section was counted. Because each field in animals
from P0 to P6 contained ~100 cells, at least 1000 cells were analyzed
at these critical time points. Because there were progressively fewer
cells per field in P21 and P90 animals (see Fig. 1), fewer cells were
analyzed, but this did not invalidate our ability to determine that
there were few apoptotic cells at these ages. When more than one animal
received the same experimental treatment, nerve sections from each
animal were mounted on separate slides, counted separately, and
averaged.
Fig. 1.
Apoptotic Schwann cells are found in neonatal but
not adult rat sciatic nerve. These are photomicrographs of longitudinal
sections of nerve, labeled by the TUNEL assay (left:
A, C, E, G) and DAPI, a nuclear counterstain
(right: B, D, F, H). There are a
few apoptotic nuclei (arrows) at P0 (A,
B) and P6 (C, D), but none at P21 (E,
F) and P90 (G, H). Scale bar, 10 µm.
[View Larger Version of this Image (113K GIF file)]
Electron microscopy. The left sciatic nerve was transected
at P1, and the rat was killed at P3. The distal nerve stump of the left
nerve, and the corresponding portion of the right sciatic nerve were
removed and fixed in 3% glutaraldehyde in 0.1 M phosphate
buffer, pH 7.4, overnight at 4°C, washed in 0.1 M
phosphate buffer, osmicated, dehydrated, and embedded in epoxy. Thin
sections were stained with uranyl acetate and lead citrate and examined
with a Zeiss electron microscope.
Western blotting and immunoprecipitation. Cultured rat
Schwann cells (Brockes et al., 1979) were treated with 20 ng/ml rhGGF2
for 2.5 min at 37°C to activate erbB receptor tyrosine
kinases. Cells were rinsed once with PBS and then incubated on ice for
10 min with chilled lysis buffer [buffer A: 50 mM Tris
HCl, pH 7.5, 150 mM NaCl, 5 mM EGTA, 1% NP40,
10% glycerol containing the protease and phosphatase inhibitors sodium
orthovanadate (1 mM), sodium molybdate (10 mM),
NaF (4 gm/l), sodium pyrophosphate decahydrate (8.8 gm/l),
phenylmethylsulfonyl fluoride (1 mM), aprotonin (10 µg/ml), and leupeptin (20 µM), all of which were added
just before use]. Lysates were collected and then clarified by
spinning in a microfuge for 10 min at 4°C. The supernatants were
aliquoted and stored at  80°C. P1 rat pups were decapitated, and
their sciatic nerves, cerebella, and cerebra were removed and
immediately frozen in liquid nitrogen. Frozen samples were diced with a
razor blade on dry ice and then homogenized with eight strokes in a
Dounce homogenizer in chilled buffer A as above. Samples were clarified
by centrifugation in a microfuge for 10 min at 4°C and stored at
80°C.
For direct Western blot analysis, samples were mixed with gel-loading
buffer containing 1 mM sodium orthovanadate, denatured (10 min, 100°C), separated on 8 cm 8% polyacrylamide Tris-glycine gels
(Novex, San Diego, CA), and blotted onto nitrocellulose. The filters
were labeled with rabbit antisera against erbB2 (Santa Cruz
SC284), erbB3 (Santa Cruz SC285), and erbB4 (one
from Santa Cruz SC283), and four different antisera from Dr. Cary Lai),
and phosphotyrosine (Transduction Laboratories). The antibodies were
detected using horseradish peroxidase-coupled antisera against rabbit
immunoglobulin and ECL reagents from Amersham (Arlington Heights, IL),
according to the their instructions, and exposed to XAR-5 film (Kodak).
Each of these antibodies gave a signal band in the size range that was
appropriate for erbB2, erbB3, and
erbB4 (~p185), as well as other bands. To determine
directly the specificity of the Santa Cruz antisera against
erbB2 and erbB3, peptide neutralization
experiments were performed on Schwann cell protein extracts following
the protocol recommended by the manufacturer. Ten micrograms of peptide
against which the antiserum was raised were incubated with 1 µg of
antiserum in a 60 µl mixture for 2 hr at room temperature. This
mixture was then diluted 1:1000 in the blocking solution used in the
hybridizations (Tris-buffered saline/1% powdered milk) and was
hybridized with a blot of Schwann cell protein extract. The band in the
p185 region of the gel was blocked by preincubation with peptide for
both erbB2 and erbB3, whereas the nonspecific
bands were not consistently affected (data not shown).
For immunoprecipitation, samples were first mixed with the
phosphotyrosine antisera (Transduction Labs) and then with
strepavidin-agarose beads (Pierce, Rockford, IL) at 4°C. The beads
were collected and washed three times in buffer A, and the
immunoprecipitates were eluted by boiling for 10 min in 2 × gel-loading buffer. The eluted samples were transferred to fresh tubes,
and equal portions were analyzed separately by Western blotting for
erbB2 or erbB3, as described above.
Immunoprecipitated Western blots had only a single band, located in the
p185 region of the gel, further documenting the specificity of the
antisera for erbB2 or erbB3.
RESULTS
Apoptotic Schwann cells are present in sciatic nerve during early
development but not at later stages
To determine whether Schwann cells undergo apoptosis during normal
development, we examined sections of rat sciatic nerve beginning at P0
through adulthood (P90) using the TUNEL assay (Gavrieli et al., 1992).
As shown in Figure 1, there were occasional
TUNEL-positive nuclei in nerves at P0 and P6; these were rarely seen by
P21, and none were seen at P90. When viewed with DAPI nuclear
counterstain, these TUNEL-positive nuclei were smaller than normal
Schwann cell nuclei and had clumped chromatin, both of which are
features of apoptotic nuclei (Kerr, 1971). There were also clusters of
round TUNEL-positive structures, probably apoptotic bodies containing
fragmented nuclei (Kerr et al., 1972). Thus, apoptosis is a prominent,
developmentally regulated feature of peripheral nerve.
Axotomy greatly increases Schwann cell apoptosis but only during
early development
To determine whether axon-Schwann cell interactions regulate
apoptosis, we transected the sciatic nerve to cause axonal
degeneration. This was carried out both during (P0 and P5) and after
(P20 and P90) the normal period of apoptosis. In the P0, P5, and P20
animals, the distal nerve stump was analyzed at 1, 2, 3, or 4 d
after axotomy; in the P90 animals, this analysis was extended to
include 8, 12, 24, and 58 d postlesion. Unlesioned nerves from
age-matched animals were used as controls. The sections were labeled
for TUNEL and counterstained with DAPI so that the proportion of
apoptotic nuclei could be determined.
The results of this experiment are summarized in Figure
2. Our counts demonstrated that between 1 and 1.2% of
the Schwann cells died by apoptosis during the first 3 d of
development. For axotomy at P0, the number of apoptotic nuclei
increased 10-fold 1 d postaxotomy, and then fell to within range
of the controls by 3 d postaxotomy. To corroborate these
observations, we compared the total number of intact nuclei in the
distal nerve stump of axotomized and aged-matched, unaxotomized
controls. There were 24% and 35% fewer nuclei in lesioned nerves at 2 and 3 d postaxotomy, respectively; this may be an underestimate of
the loss of Schwann cells, because macrophages are known to infiltrate
degenerating nerves (Griffin and Hoffman, 1993). Axotomy at P5 resulted
in a smaller (threefold) increase in the number of apoptotic nuclei at
1 d postaxotomy, followed by a decline to control levels (Fig. 2).
Unlike axotomy at P0, however, there was no significant decline in the
total number of nuclei at any of the time points after axotomy (data
not shown). Axotomy at P20 (examined at 1 and 4 d postaxotomy) or
P90 (examined at 1, 4, 8, 12, 24, and 60 d postaxotomy; data not
shown) did not cause an increased number of apoptotic nuclei. These
data indicate that there may be a window of susceptibility to
axotomy-induced apoptosis in developing nerve, and the timing of this
window corresponds to the normal period of Schwann cell apoptosis
during development.
Fig. 2.
Axotomy increases Schwann cell apoptosis during
early development. The distal nerve stumps of sciatic nerves that were
transected at P0, P5, and P20 (cross-hatched bars), and
age-matched unlesioned nerves (solid bars) were removed
and processed for detection of apoptosis by the TUNEL assay. The data
represent the mean percentage of apoptotic cells in 10 representative
fields from three to four sections of each nerve. Error bars represent
SEM.
[View Larger Version of this Image (14K GIF file)]
To evaluate further Schwann cell apoptosis after axotomy, we performed
electron microscopy (Fig. 3) on the distal nerve stumps
of P3 sciatic nerves that had been axotomized 2 d earlier (at P1),
as well as on age-matched, unlesioned nerves. In lesioned nerves, most
Schwann cells were not associated with any axons, indicating that most
axons had already degenerated. Nearly all of the remaining axons had
abnormal ultrastructural features, such as accumulations of dense
bodies, neurofilaments, or smooth endoplasmic reticulum, indicating
that they were degenerating (Griffin and Hoffman, 1993). There were
several apoptotic nuclei per section in the lesioned nerves, and none
in the unlesioned nerves. The apoptotic nuclei appeared to be within
Schwann cells, because they were found within basal laminae; they were
not surrounded by an extra cell membrane, which would be expected if
they had been phagocytosed by other Schwann cells or macrophages.
Unlike normal Schwann cell nuclei, apoptotic nuclei had large amounts
of heterochromatin apposed to the inner aspect of the nuclear membrane,
and at more advanced stages, the chromatin and Schwann cell cytoplasm
became electron-lucent. This sequence of degenerative changes in the
nucleus and cytoplasm is characteristic of apoptosis in other cell
types (Kerr, 1971; Kerr et al., 1972; Arends et al., 1990), and hence
confirms that denervation leads to apoptosis in neonatal sciatic nerve.
Fig. 3.
Electron microscopy of apoptotic Schwann cells.
These are electron micrographs of Schwann cell nuclei in the distal
nerve stump of a P3 rat sciatic nerve, 2 d after transection.
A shows a normal Schwann cell nucleus that is associated
with a degenerating axon (ax). B-D show
apoptotic nuclei in various stages of degeneration. All of the nuclei
in B-D have condensed chromatin on the inside of the
nuclear membrane. In addition, the nucleoplasm is rarified in
C and D, and cytoplasm
(cy) is rarified in D. The
arrows in C indicate an apparent
separation of the nucleus into two fragments. In all panels, the
arrowheads point to the basal lamina. Scale bars, 1 µm.
[View Larger Version of this Image (79K GIF file)]
Apoptotic Schwann cells display a predominately
premyelinating phenotype
To determine the phenotype of apoptotic cells, we used
immunofluorescence to double-label TUNEL-positive nuclei with a panel
of Schwann cell markers. Neonatal nerves contain cells that are
destined to become either myelinating or nonmyelinating Schwann
cells. We stained sections of P0 and P6 nerves for the pan-Schwann cell
marker S100, the low-affinity NGFR/p75, which stains premyelinating
and nonmyelinating Schwann cells, and periaxin, which is one of the
earliest markers of myelinating Schwann cells (Stemple and Anderson,
1991; Gillespie et al., 1994; Scherer et al., 1995). We determined
whether a TUNEL-positive nucleus was within a S100-, NGFR/p75-, or
periaxin-positive cell by focusing through each TUNEL-positive cell
using conventional epifluorescence. In photographing these sections,
however, both conventional epifluorescence and confocal microscopy with
image stacking gave less than optimal results. Instead, as shown in
Figure 4, we photographed single optical sections with a
confocal microscope and enhanced the brightness of the rhodamine signal
to make it clearly visible.
Fig. 4.
The immunophenotype of apoptotic Schwann cells in
normal development and 1 d postaxotomy. These are confocal
photomicrographs of sections taken from nerves transected at P0
(right), or their contralateral unlesioned counterparts
(left). The sections were labeled for TUNEL (rhodamine)
as well as S100 (A, B), NGFR (C, D),
periaxin (E, F), or erbB2
(G, H), which were visualized with fluorescein
optics. These confocal images were enhanced to make the TUNEL-positive
cells more visible, with the untoward effect of making the nucleus
appear to ``pop out'' of the fluorescein-positive cytoplasm.
TUNEL-positive nuclei are seen within fluorescently labeled cells for
the S100-, NGFR-, and erbB2-labeled sections.
Fluorescently labeled cells with TUNEL-negative nuclei appear as dark
spaces within the cells (arrows). In E
and F, the TUNEL-positive nuclei are not seen within the
periaxin-labeled cells. Together, these photomicrographs demonstrate
that the TUNEL-positive cells are Schwann cells (S100-positive),
mostly premyelinating (erbB2-positive and NGFR-positive,
but periaxin-negative). Scale bar, 10 µm.
[View Larger Version of this Image (120K GIF file)]
Nearly all of the apoptotic nuclei were found in S100-positive
cells, demonstrating that they were Schwann cells. When viewed by
conventional epifluorescence, one could clearly see TUNEL-positive
nuclei surrounded by S100-immunoreactivity (Fig.
4A), although in many cells the
S100-immunoreactivity extended into the nucleus (Mata et al., 1990).
Most TUNEL-positive nuclei were contained within the NGFR/p75-positive
cells (Fig. 4C), indicating that they were in premyelinating
Schwann cells. In the periaxin-labeled sections, positive nuclei
appeared adjacent to but not within the fluorescently labeled cells,
with few exceptions (Fig. 4E). These results
demonstrate that during normal development, myelinating Schwann cells
are relatively less likely to undergo apoptosis than premyelinating
Schwann cells.
We also determined the phenotype of TUNEL-positive cells in lesioned
neonatal nerves. For these experiments, we analyzed nerves from P1
animals 1 d postaxotomy, at the peak of Schwann cell apoptosis,
because the large number of TUNEL-positive cells permitted a
quantitative analysis. Although the dense packing of Schwann cells in
neonatal nerves made it difficult to determine the immunophenotype of
every TUNEL-positive cell, >90% of the cells containing apoptotic
nuclei were NGFR-positive (n = 132; SE = 4%); one
example is shown in Figure 4D. Less than 8% were
periaxin-positive (n = 160; SE = 3%); one example
is shown in Figure 4F. Thus, in both unlesioned and
axotomized nerves, the overwhelming majority of apoptotic Schwann cells
have a premyelinating phenotype characterized by S100 and NGFR/p75
expression (Jessen and Mirsky, 1992), but only a subset of Schwann
cells with this phenotype seems to undergo apoptosis.
Premyelinating Schwann cells express erbB2 and
erbB3, which are phosphorylated
To evaluate further our results regarding the effects of
neuregulin on apoptosis (see below), we also wished to determine
whether apoptotic Schwann cells in vivo expressed a
neuregulin receptor. We have shown previously that premyelinating but
not myelinating Schwann cells express erbB2 (Cohen et al.,
1992), which needs either erbB3 or erbB4 to form
a heterodimeric receptor for neuregulin (Carraway and Cantley, 1994;
Carraway and Burden, 1995; Marchionni, 1995). To determine whether
these receptor components were present in neonatal nerves, we performed
Western blot analysis and immunohistochemistry of neonatal rat sciatic
nerves. By Western blot (Fig. 5A), although
erbB2 and erbB3 were readily detected,
erbB4 was not detected. In adult sciatic nerves, the level
of erbB2 was substantially lower than in neonatal nerves,
whereas the level of erbB3 was relatively unchanged (Fig.
5A). These results were confirmed by the use of additional
antisera against erbB2, erbB3, and
erbB4, and by blocking experiments using the specific
peptides against which the antisera were raised (data not shown).
Fig. 5.
Expression and activation of neuregulin receptors
in peripheral nerve glia. Lysates of cultured rat Schwann cells and
homogenates of P0 and adult rat tissues were analyzed by Western
blotting and immunoprecipitation as described in Materials and Methods.
All panels display the p185 region of the gels. A shows
the expression of erbB2, erbB3, and
erbB4. Both erbB2 and
erbB3 are readily detected in cultured Schwann cells and
in sciatic nerve. The level of erbB2 declines in adult
sciatic nerve more so than that of erbB3.
ErbB4 was not detected in Schwann cells or sciatic
nerve, whereas it was detected readily in the cerebrum and cerebellum.
B shows the presence of phosphotyrosine in Schwann cells
treated with rhGGF2, as well as P0 sciatic nerve, cerebrum, and
cerebellum, but not in untreated Schwann cells or adult sciatic nerve.
C shows the result of the immunoprecipitation
experiment. The left lane is a protein extract from
Schwann cells; the three lanes that are
underlined are phosphotyrosine immunoprecipitates from
rhGGF2-treated (+) or untreated () Schwann cells and P0 rat sciatic
nerve. Note that P0 sciatic nerve contains phosphorylated
erbB2 and erbB3, and that treatment with
rhGGF2 increased the amount of phosphorylated erbB2 and
erbB3 in Schwann cells.
[View Larger Version of this Image (22K GIF file)]
To localize erbB2, erbB3, and erbB4 in
neonatal nerves, we used a number of different antisera. None of the
antisera against erbB3 or erbB4 labeled cells in
sections of neonatal nerves, regardless of whether the nerve was
unfixed or fixed in paraformaldehyde or Zamboni's solution, even
though we had demonstrated that erbB3 was present by Western
blot analysis. Several monoclonal and polyclonal antibodies against
erbB2, however, labeled Schwann cells, which was documented
further by the double-labeling with antisera against S100 (data not
shown). Although perineurial cells were also erbB2-positive,
they make only a small contribution to the total amount of
erbB2-positivity in neonatal nerve, so that the Western blot
analysis (see below) mostly reflects the contribution of Schwann cells.
In double-labeling experiments for TUNEL and erbB2, most
TUNEL-positive nuclei were found in erbB2-positive cells in
both unlesioned and lesioned neonatal nerves (Fig.
4G,H). These data, taken together, indicate that
premyelinating Schwann cells express erbB2 and
erbB3, and that some of these cells undergo apoptosis during
normal development and after neonatal axotomy.
Because premyelinating Schwann cells seemed to have a functional
neuregulin receptor, we examined the possibility that this receptor is
phosphorylated in vivo by endogenous neuregulins, because
binding of the erbB3 receptor in other cell types leads to
phosphorylation of both erbB2 and erbB3 (Carraway
and Cantley, 1994; Carraway and Burden, 1995). Western blots were
prepared from the same material used to detect erbB2 and
erbB3 and probed with a polyclonal antibody that recognizes
phosphotyrosine residues. As shown in Figure 5B, neonatal
but not adult sciatic nerve contained a phosphorylated protein of the
appropriate size for either erbB2 or erbB3
(~185 kDa), indicating that one or both of these proteins were
phosphorylated in premyelinating Schwann cells. To demonstrate
conclusively that this phosphorylated protein was erbB2
and/or erbB3, the same homogenate of neonatal nerves was
immunoprecipitated with the antiphosphotyrosine polyclonal antibody,
separated on a polyacrylamide gel, transferred to a nitrocellulose
membrane, and probed for erbB2 and erbB3 (Fig.
5C). Protein extracts from cultured rat Schwann cells, which
express both erbB2 and erbB3 (Levi et al., 1995),
that had been grown in unsupplemented medium or medium supplemented
with neuregulin, were used as negative and positive controls,
respectively, for phosphorylated erbB2 and erbB3.
Figure 5C demonstrates that both erbB2 and
erbB3 are phosphorylated in neonatal sciatic nerve,
indicating that these receptors are activated in vivo by
endogenous neuregulins. In control immunoprecipitations, we determined
that the detection of phosphorylated receptors requires inclusion of
the primary antiphosphotyrosine antibody.
Apoptosis after axotomy and during normal development is prevented
by addition of exogenous neuregulin
The observations that Schwann cell precursors die in
vitro after the withdrawal of growth factors, including
neuregulins (Dong et al., 1995), and that neuregulins are made by PNS
neurons and are axonally transported (Marchionni et al., 1993; Sandrock
et al., 1995), raise the possibility that neuregulin regulates Schwann
cell apoptosis in developing nerves. Axotomy could cause apoptosis by
removing the axonal source of neuregulin, and exogenous neuregulin
could rescue axotomized Schwann cells, as recently observed by
Trachtenberg and Thompson (1996), at the neuromuscular junction. We
tested this idea by injecting neuregulin into the axotomized (left) leg
to maximize the availability of neuregulin to the axotomized Schwann
cells in the distal nerve stump. Because the optimal amount of
neuregulin, dosing frequency, and route of administration are not
established, we arbitrarily chose to inject 1 µg/gm body mass of
neuregulin before, during, and after axotomy. We used a highly
purified, recombinant secreted isoform of human neuregulin, termed
rhGGF2 (Marchionni et al., 1993). Because the amount of axotomy-induced
apoptosis is higher at birth, and the perineurial barrier is less
developed in neonatal animals (Thomas and Olsson, 1984), we used pups
at the youngest age possible, the day of birth. One litter of 12 newborn rats was used. Each experimental group consisted of three pups:
one group was axotomized and treated with neuregulin; one group was
axotomized and treated with vehicle alone; one group was not axotomized
and treated with neuregulin; and one group was not axotomized and
was injected with vehicle. All of the animals were killed 24 hr after
axotomy, the time at which the number of TUNEL-positive nuclei was
maximal (Fig. 2). Figure 6 shows a representative field
from an axotomized animal that received vehicle alone and another field
from an axotomized animal that was treated with neuregulin. Axotomized
nerves that had received vehicle alone had many apoptotic Schwann
cells, whereas axotomized nerves that received neuregulin had even
fewer apoptotic cells than unlesioned nerves.
Fig. 6.
Neuregulin prevents Schwann cell apoptosis after
axotomy. These are photomicrographs of longitudinal sections taken from
sciatic nerve, 1 d after transection. A, C, and
E are from a vehicle-only treated animal, whereas
B, D, and F are from an animal treated
with neuregulin. A and B show TUNEL
staining; TUNEL-positive nuclei are indicated by
arrowheads. Note that there are no apoptotic nuclei in
the neuregulin-treated nerve. C and D
show the DAPI counterstained nuclei; the arrows show
that the TUNEL-positive nuclei (as in A) are fragmented.
E and F show S100 staining; the
arrowheads indicate the location of the apoptotic
nuclei, which appear as a dark void within the Schwann cell cytoplasm.
Scale bar, 10 µm.
[View Larger Version of this Image (121K GIF file)]
To evaluate these results quantitatively, we determined the percentage
of apoptotic Schwann cells in each experimental group; these are
tabulated in Table 1. The most striking result was that
in neuregulin-treated animals, axotomy did not increase the number of
TUNEL-positive nuclei. This effect cannot be attributed to the vehicle,
because there was a 10-fold increase in the number of apoptotic Schwann
cells after axotomy in animals treated with vehicle alone, comparable
to the increase described above (Fig. 2) after axotomy at P0.
Neuregulin also seemed to lower the endogenous rate of apoptosis in
developing Schwann cells. In unlesioned nerves, there were
significantly fewer apoptotic Schwann cells after neuregulin
administration than after treatment with vehicle alone
(p < 0.05). In addition, the number of
apoptotic Schwann cells found in the right sciatic nerve of the animal,
which was never injected, tended to be lower in neuregulin-injected
animals than in vehicle-injected animals, regardless of whether the
left nerve was transected, but these differences did not achieve
statistical significance. These results demonstrate that apoptotic
Schwann cells can be rescued by neuregulin and are thus not destined to
die. Rather, the number of Schwann cells in developing nerves seems to
be molded by axon-Schwann cell interactions. Neuregulin thus may be
one of the axonally derived factors that mediate Schwann cell survival.
Table 1.
Neuregulin prevents apoptosis in P1 sciatic nerves
axotomized for 1 d
| Treatment |
%
TUNEL-positive nuclei
|
| Transected (left) side |
Untransected (right)
side |
|
| Transection, no
neuregulin |
9.44% ± 3.15 |
1.66%
± 0.28 |
| Transection, plus neuregulin |
0.72%
± 0.24a |
0.97%
± 0.23b |
| No transection, no
neuregulin |
1.68% ± 0.54 |
2.40% ± 0.41 |
| No transection,
plus neuregulin |
0.38%
± 0.23c |
1.68%
± 0.39d |
|
|
Newborn rats were divided into four treatment groups, three
animals per group (see Materials and Methods). One day after
transection, the distal stumps from transected nerves, the
corresponding segment from unlesioned nerves, and the contralateral
nerves were removed and processed for the TUNEL assay. TUNEL-positive
nuclei were counted, and their percentage of the total was calculated
(see Materials and Methods). The % TUNEL-positive nuclei in the left
and right sciatic nerves from animals that received neuregulin were
compared with those in animals that received vehicle alone by a paired,
two-tailed t test.
|
|
a
The number of apoptotic cells in transected
nerves from animals that received neuregulin was significantly less
than that in transected nerves from animals that received vehicle alone
(p < 0.0001).
|
|
b,d Although neuregulin reduced the percentage
of TUNEL-positive cells in the contralateral leg in both the transected
and the nontransected animals, this reduction did not achieve
statistical significance in either group.
|
|
c
The number of apoptotic cells in
nontransected nerves from animals that received neuregulin was
significantaly less than that in nontransected nerves from animals that
received vehicle alone (p < 0.05).
|
|
DISCUSSION
Our results demonstrate that there is a transient period in
developing nerves during which 1% of the Schwann cells undergo
apoptosis. In this developmental window, Schwann cell apoptosis can be
augmented 10-fold by axotomy, demonstrating that survival is regulated
by axon-Schwann cell interactions. During normal development and after
axotomy, the cell death is limited to premyelinating Schwann cells.
Administration of exogenous neuregulin prevents apoptosis after axotomy
and also lowers the endogenous rate of apoptosis during development.
Premyelinating Schwann cells probably express a neuregulin receptor
composed of erbB2 and erbB3, and both of these
receptor subunits are phosphorylated in vivo, presumably in
response to endogenous neuregulin. These data suggest that axonally
derived neuregulin regulates apoptosis in premyelinating Schwann cells
during the development of peripheral nerve, via an erbB2 and
erbB3 neuregulin receptor, and extend the known actions of
neuregulins on the biology of Schwann cells.
Premyelinating Schwann cells undergo apoptosis
That Schwann cells undergo apoptosis has been recognized only
recently. Jessen and colleagues found apoptosis in cultured Schwann
cell precursors that are deprived of growth factors (Jessen et al.,
1994; Dong et al., 1995; Gavrilovic et al., 1995). In these apoptotic
precursors, the chromatin condenses in the characteristic way, and the
DNA is nicked (Jessen et al., 1994). These precursors do not express
S100, galactocerebroside, or sulfatide, and are earliest stages of
developing Schwann cells (Jessen et al., 1994; Jessen and Mirsky, 1991,
1992; Stewart et al., 1995). Cultured precursors die unless FGF, IGF-1,
or neuregulin is added to the medium; neuregulin is the most potent
factor yet tested.
The apoptotic Schwann cells that we have found in neonatal nerves,
however, are not Schwann cell precursors. Precursors are present
transiently in embryonic nerves and do not express S100 (Jessen and
Mirsky, 1992; Jessen et al., 1994; Stewart et al., 1995). In contrast,
we and others (Trachtenberg and Thompson, 1996) have found apoptotic
cells in neonatal nerves, in cells that expressed S100. We further
characterized these apoptotic Schwann cells by showing that they were
predominately premyelinating, because they expressed NGFR/p75 and not
periaxin, one of the first myelin-related proteins expressed by
myelinating Schwann cells (Gillespie et al., 1994; Scherer et al.,
1995). These data indicate that there is a subpopulation of
premyelinating Schwann cells in neonatal nerves that is susceptible to
apoptosis, and that these cells disappear after the initial stages of
development. Because Schwann cells are proliferating during the period
of apoptosis (Brown and Asbury, 1981; Stewart et al., 1993), perhaps
newly generated cells are the susceptible ones, as has been described
in immature oligodendrocytes and stem cells in the subventricular zone
(Barres et al., 1992; Morshead and van der Kooy, 1992). If newly
generated Schwann cells require axonally derived neuregulins for their
survival, then the occasional Schwann cells without axonal contact that
we have observed in neonatal rodent nerves by electron microscopy (S.S.
Scherer, personal observation) would be vulnerable. Whether these
supernumerary Schwann cells are newly generated and the ones that are
eliminated by apoptosis remains to be determined.
Developing Schwann cells and oligodendroglia undergo axonally
dependent apoptosis
After axotomy, there was a rapid and striking increase in the
number of apoptotic Schwann cells, but only in neonatal nerves. When
transection was performed within the first week after birth, the number
of apoptotic cells increased 10-fold within 1 d after transection.
The number of apoptotic cells rapidly fell, so that 3 d after
transection the number was back to baseline. As in unlesioned nerves,
the apoptotic Schwann cells had a premyelinating phenotype. Our
observations agree with those of Trachtenberg and Thompson (1996), who
found that all terminal Schwann cells at developing neuromuscular
junctions underwent apoptosis after axotomy, which was completely
prevented by exogenous neuregulin. These workers did not evaluate the
phenotype of the apoptotic Schwann cells and did not report apoptotic
Schwann cells during normal development. In older animals, Schwann cell
apoptosis was rarely detected in nontransected nerves and did not
increase after axotomy. Our observations do not exclude the possibility
that Schwann cells undergo apoptosis after transection of adult nerves,
because Schwann cells seem to disappear slowly from the distal nerve
stumps of chronically denervated nerves (Weinberg and Spencer, 1978).
Our method of detecting apoptotic cells provides a snapshot of
apoptosis and could easily miss a more protracted loss of cells.
Cell death during development and after axotomy has been reported in
developing oligodendrocytes, although the methods used to identify the
dead cells did not detect apoptosis per se (Barres et al., 1992,
1993a,b). As in Schwann cells, the proportion of dead oligodendrocytes
in the optic nerve is higher during early development, both during
normal development and after axotomy, although the time frame of
accumulation and clearing of dead cells continues for several weeks. As
in apoptotic Schwann cells, the oligodendrocytes that died after
axotomy were unlikely to have made myelin sheaths. Finally, both
developing oligodendrocytes and Schwann cells can be rescued by
axonally derived trophic factors, which have been shown previously to
modulate their particular maturation in vitro. Normal cell
death of oligodendrocytes in vivo can be suppressed by the
delivery of exogenous platelet-derived growth factor (PDGF) and ciliary
neurotrophic factor (CNTF) (Barres et al., 1993b). CNTF or IGF-1 will
also rescue axon-deprived oligodendroglia (Barres et al., 1993a).
Neuregulin regulates axon-Schwann cell interactions
Many aspects of Schwann cell development may be regulated by
axon-Schwann cell interactions (Stewart et al., 1995; Scherer and
Salzer, 1996). It is becoming increasingly clear that neuregulin may be
one of the main mediators of these interactions, especially of the
early events of Schwann cell development. It promotes the
differentiation of Schwann cells from the neural crest (Shah et al.,
1994), induces proliferation in precursors and neonatal and adult
Schwann cells (Lemke, 1990; Eccleston, 1992; Levi et al., 1995;
Rutkowski et al., 1995), and prevents apoptosis of precursors and
neonatal Schwann cells (Dong et al., 1995; Trachtenberg and Thompson,
1996). The recent observation that Schwann cell precursors are
deficient in mice lacking neuregulin attributable to disruption of the
neuregulin gene (Meyer and Birchmeier, 1995) confirms that neuregulin
plays an essential role in the early biology of Schwann cells.
There is accumulating evidence demonstrating that the effects of
neuregulins on Schwann cells are mediated by the neuregulin receptor
composed of erbB2 and erbB3. Previous workers
have shown that neural crest cells, Schwann cell precursors, and
premyelinating Schwann cells, but not myelinating Schwann cells,
express erbB2 (Cohen et al., 1992; Shah et al., 1994; Dong
et al., 1995). We found erbB2 and erbB3, but not
erbB4, in neonatal nerves, suggesting that erbB2
and erbB3 form the neuregulin receptor in neonatal Schwann
cells. These results are consistent with those of Levi et al. (1995),
who detected erbB2 and erbB3 but not
erbB4 in cultured human Schwann cells by Western blot
analysis, and erbB2 and erbB3 mRNA, as well as a
lower level of erbB4 mRNA, by reverse transcription-PCR. It
is likely that both erbB2 and erbB3 are needed to
form a functional neuregulin receptor, because erbB2 does
not directly bind neuregulins but is activated by interacting with
erbB3, which can bind neuregulins, but by itself seems to be
incapable of transducing a signal (Carraway and Cantley, 1994; Carraway
and Burden, 1995; Marchionni, 1995). If this is the case, then the fall
in erbB2 expression during development may account for the
lack of effect of neuregulin on maturing Schwann cells.
Like other receptor protein-tyrosine kinases (van der Geer et al.,
1994), erbB2 and erbB3 are activated by
phosphorylation (Carraway and Burden, 1995). Neuregulin leads to
phosphorylation of erbB2 in cultured Schwann cells (Levi et
al., 1995), and antibodies against erbB2 inhibit its
phosphorylation and the effects of neuregulins on proliferation
in vitro (Levi et al., 1995; Morrissey et al., 1995). Our
demonstration that both erbB2 and erbB3 are
phosphorylated in vivo in neonatal but not adult sciatic
nerves is strong evidence that neuregulins are present in neonatal
nerves and available to Schwann cells. Axons are the most abundant
source of neuregulins in nerve (Sandrock et al., 1995), but exactly
which isoforms are expressed by axons remains to be determined.
Although there are other potential neuronal trophic factors for Schwann
cells, including acidic FGF (Eckenstein et al., 1990), PDGF (Yeh et
al., 1991), and gas6 (Li et al., 1996), neuregulin is the best example
to date of a neuronal trophic factor that affects the development of
Schwann cells.
The discovery of trophic factors for Schwann cells that are derived
from PNS neurons reinforces the possibility that there are reciprocal
trophic interactions between these cells (Reynolds and Woolf, 1993). If
Schwann cells make survival factors for neurons during development, and
neuronal trophic factors, in turn, support the survival of Schwann
cells, then there would be a system for matching the numbers of neurons
and Schwann cells during development (Cowan et al., 1984). In keeping
with this proposal, Verdi et al. (1996) recently reported that cultured
sympathetic neuroblasts provide neuregulins for non-neuronal cells,
which in turn provide NT-3 for the neuroblasts. Reciprocal
axon-Schwann cell interactions could also be involved in axonal
regeneration in the PNS. It has long been appreciated that Schwann
cells make trophic factors that seem to support the survival and alter
the phenotype of PNS neurons during the process of axonal regeneration
(Scherer and Salzer, 1996). The expression of neuregulins by
regenerating axons, in turn, could regulate the proliferation and
survival of Schwann cells in the distal nerve stump, because axotomy
causes Schwann cells to reexpress erbB2 (Cohen et al.,
1992).
FOOTNOTES
Received May 24, 1996; revised July 8, 1996; accepted July 15, 1996.
This work was supported by grants from National Institutes of Health
(NS08075, NS34528, and NS01565 to S.S.S.; NS01793 to J.B.G.) and by the
National Multiple Sclerosis Society (RG 2153-B3 to J.B.G.). We thank
Shelly Whyatt, Kristen Cronin, and Tracey Oliver for technical
assistance; Drs. Eugene Johnson, Peter Brophy, Kermit Carraway, and
Cary Lai for their generous gifts of antibodies against NGFR/p75,
periaxin, erbB3, and erbB4, respectively;
Yunhee Kim Kwon and Charles Stiles for advice on methods for
homogenization of frozen tissues that preserve phosphorylated
tyrosines; Maria Pita for artwork; and Lynn Rutkowski and David
Pleasure for their critical reading of this manuscript.
Correspondence should be addressed to Dr. Judith B. Grinspan, Division
of Neurological Research, Children's Hospital of Philadelphia, 3517 Civic Center Boulevard, Philadelphia, PA 19104.
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