 |
 Previous Article | Next Article 
The Journal of Neuroscience, May 1, 1998, 18(9):3344-3350
Bcl-2 Accelerates the Maturation of Early Sensory Neurons
Gayle
Middleton,
Luzia
G. P. Piñón,
Sean
Wyatt, and
Alun M.
Davies
School of Biological and Medical Sciences, Bute Medical Buildings,
University of St. Andrews, St. Andrews, Fife KY16 9AJ, Scotland.
 |
ABSTRACT |
Bcl-2 is a cytoplasmic protein that blocks apoptosis in a wide
variety of cell types. Here we report a novel role for Bcl-2 in the
early stages of neuronal development. Shortly after differentiating from progenitor cells, sensory neurons undergo a distinct morphological change; initially they have small, spindle-shaped, phase-dark cell
bodies that become large, spherical, and phase-bright. Early sensory
neurons cultured from the trigeminal ganglia of
bcl-2 / embryos at embryonic day
11 (E11) and E12 underwent this change more slowly than trigeminal
neurons of wild-type embryos of the same ages. The delay was not
attributable to the well documented role of Bcl-2 in preventing
apoptosis, because Bcl-2-deficient early sensory neurons survived as
well as wild-type neurons. Accordingly, there was a significantly
smaller number of the more mature type of neuron in the early
trigeminal ganglia of bcl-2/
embryos, yet the number of neurons in the trigeminal ganglia of
bcl-2/ and wild-type embryos was
similar. The absence of Bcl-2 did not cause a uniform delay in the
developmental program of sensory neurons, because the time course of
nerve growth factor receptor expression (both trkA and p75) was
unaffected in the trigeminal neurons of
bcl-2/ embryos. These findings
indicate that Bcl-2 expression is required for the normal progression
of a particular early maturational change in embryonic sensory
neurons.
Key words:
Bcl-2; neuronal differentiation; apoptosis; neurotrophin; sensory neuron; gene-targeted mice
| |
INTRODUCTION |
Bcl-2 is a widely expressed
cytoplasmic protein that plays a key role in regulating cell survival
in the immune system and nervous system. Mice with targeted null
mutations in the bcl-2 gene have markedly reduced numbers of
B and T cells attributable to increased apoptosis (Nakayama et al.,
1993 , 1994; Veis et al., 1993), whereas mice carrying a transgene
causing high levels of Bcl-2 expression in the immune system show
extended survival of B and T cells (McDonnell et al., 1989, 1990).
Overexpression of Bcl-2 in cultured neurons prevents their death after
neurotrophin deprivation (Garcia et al., 1992; Allsopp et al., 1993b),
and mice expressing a bcl-2 transgene under the control of a
neuron-specific enolase promoter have increased numbers of neurons in
several regions (Martinou et al., 1994). The survival response of
cultured cranial sensory neurons to neurotrophins during the phase of
naturally occurring neuronal death is markedly reduced by antisense
bcl-2 RNA (Allsopp et al., 1995). Likewise, cranial sensory
neurons from bcl-2/ embryos do not
survive as well in vitro with neurotrophins as wild-type
embryos during the peak period of naturally occurring neuronal death
and are lost to a greater extent than wild-type neurons during this
period of development in vivo (Piñón et al.,
1997). Sympathetic neurons from postnatal
bcl-2/ mice die more rapidly
after nerve growth factor (NGF) deprivation in vitro
than wild-type neurons (Greenlund et al., 1995), and postnatal
bcl-2/ mice have significantly fewer
sensory, autonomic, and motor neurons than wild-type mice (Michaelidis
et al., 1996). Furthermore, Bcl-2 is structurally and functionally
similar to the ced-9 gene product of Caenorhabditis
elegans that also prevents programmed cell death (Hengartner
and Horvitz, 1994).
In addition to the wealth of data indicating that Bcl-2 plays a key
role in regulating cell survival, work on several cell lines has raised
the possibility that Bcl-2 influences neuronal differentiation. Bcl-2
overexpression in a neural crest-derived line enhances neurite
outgrowth and increases the expression of neuron-specific enolase
(Zhang et al., 1996). Midbrain-derived dopaminergic lines stably
expressing Bcl-2 extended longer neurites than control-transfected
cells (Oh et al., 1996), and Bcl-2 enhances the differentiation of the
PC12 cells grown in serum-free conditions (Batistatou et al.,
1993).
Because the developmental significance of overexpressing Bcl-2 in cell
lines is difficult to interpret, we compared the early development of
newly differentiated sensory neurons of
bcl-2/ and wild-type mouse embryos.
Shortly after sensory neurons differentiate from progenitor cells, they
undergo a distinctive and clearly recognized morphological change;
initially they have small, spindle-shaped, phase-dark cell bodies that
subsequently enlarge and become spherical and phase-bright (Wright et
al., 1992). We show that Bcl-2-deficient neurons retain a more immature
morphology longer than wild-type neurons both in vitro and
in vivo, and that this delay in early neuronal maturation is
not a consequence of the antiapoptotic function of Bcl-2.
| |
MATERIALS AND METHODS |
Experimental animals. Bcl-2 null mutant mice were a
gift of Dennis Loh, Nippon Roche Research Center, Kamakura, Japan
(Nakayama et al., 1993, 1994). Embryos were obtained from overnight
matings of bcl-2+/ mice. Pregnant
females were killed at the required stage of gestation, and the
genotypes of the embryos were determined by a PCR-based technique using
DNA isolated from embryonic tissues. There were no consistent
differences in the stage of development of wild-type and
Bcl-2-deficient embryos in each litter using the staging criteria of
Theiler (1972).
Neuronal cultures. Separate dissociated cultures of
trigeminal ganglion neurons were established from each embryo in E11
and E12 litters resulting from matings of
bcl-2+/ mice. The trigeminal neurons of
each embryo were cultured in triplicate in 60-mm-diameter
poly-D-ornithine- and laminin-coated plastic tissue culture
dishes at a density of 500-2000 neurons per dish in 5 ml of serum-free
medium (Davies et al., 1993). Because many trigeminal neurons switch
survival dependence from brain-derived neurotrophic factor (BDNF) to
NGF between E11 and E12 (Buchman and Davies, 1993; Paul and Davies,
1995), E11 neurons were grown with BDNF (5 ng/ml), and E12 neurons were
grown with NGF (5 ng/ml).
Cohorts of morphologically immature neurons were defined in these
cultures 18 hr after plating, and the fate of each neuron in these
cohorts was followed for up to 3 d in culture. This was done by
recording the location 18 hr after plating of all immature neurons
within a 9 × 9 mm grid inscribed on the undersurface of the
culture dishes (Davies, 1989) and by monitoring at intervals if each of
these neurons was still immature, had assumed a more mature morphology,
or had degenerated.
Quantification of neurons in the trigeminal ganglion. E12,
E13, and E14 mouse embryos in litters resulting from overnight matings
of bcl-2+/ mice were fixed in 4%
paraformaldehyde in 0.1 M phosphate buffer, pH 7.3, and
then embedded, serially sectioned at 8 µm, and stained with cresyl
fast violet, and the total number of morphologically recognizable
neurons in both trigeminal ganglia was quantified as described
previously (Piñón et al., 1996). Neurons were identified by
virtue of Nissl substance and large, round, pale-stained nuclei. Because of their small size, immature neurons cannot be distinguished from progenitor cells and glial cells in sections stained with cresyl
fast violet and are therefore not included in these counts.
To identify all neurons (immature and mature) in the trigeminal ganglia
of younger embryos, neurofilament staining was used. The heads of E12
embryos were fixed in Carnoy's fluid (60% ethanol, 30% chloroform,
and 10% acetic acid) for 20 min before dehydration and wax embedding.
Serial sections of the heads were cut at 8 µm, mounted on
poly-L-lysine-coated slides, cleared in xylene, and
dehydrated before quenching (10% methanol and 3% hydrogen peroxide in
PBS). Nonspecific interactions were blocked using 10% horse serum in
PBS with 0.4% Triton X-100. The sections were incubated in primary
antibody (monoclonal anti-neurofilament 160; Sigma, St. Louis, MO)
(used at 1:500) for 1 hr and then labeled using biotinylated secondary
antibody (1:200), avidin, and biotinylated horseradish peroxidase
macromolecular complex (Vectastain ABC kit; Vector Laboratories,
Burlingame, CA). The substrate used for the peroxidase reaction was 1 mg/ml diaminobenzidine tetrachloride (Sigma). After staining, the
sections were washed in tap water before rehydration and mounting.
Estimation of neuronal number was performed as for cresyl fast
violet-stained sections (Piñón et al., 1996). Here, neurons
were identified as neurofilament-positive cells.
Measurement of specific mRNA levels. A quantitative reverse
transcription-PCR (RT-PCR) technique was used to measure the levels of
trkA and p75 mRNAs in total RNA extracted from pairs of trigeminal ganglia dissected from wild-type and
bcl-2/ mice (Wyatt and Davies, 1993).
The reverse transcription and PCR reactions were calibrated by the
inclusion of known amounts of cRNA competitor templates for each of the
mRNAs in the reverse transcription reaction. The cRNA competitor
templates were synthesized in vitro from cDNA competitor
constructs. Details of the competitors, primers, and reaction
conditions are provided elsewhere (Wyatt and Davies, 1993, 1995; Wyatt
et al., 1997). Previous detailed comparisons of this method with
quantitative Northern blotting have demonstrated its accuracy and
reproducibility over a wide range of mRNA concentrations (Wyatt and
Davies, 1993).
| |
RESULTS |
Neuronal maturation in vitro
Sensory neurons undergo a clearly recognized morphological change
at an early stage in their development. After differentiating from
progenitor cells, sensory neurons initially have small, spindle-shaped, phase-dark cell bodies. Subsequently, the cell bodies enlarge to become
spherical and phase-bright (Wright et al., 1992). We refer to
developing sensory neurons exhibiting these two morphologically distinct appearances as immature and mature early sensory neurons, respectively (Fig. 1). In the current
study, we have focused on this morphological change in the embryonic
mouse trigeminal ganglion, a population of sensory neurons in which
development is extensively characterized (Davies and Lumsden, 1984,
1986; Davies, 1987; Piñón et al., 1996; Wilkinson et al.,
1996). The majority of neurons in this ganglion differentiate from
proliferating progenitor cells between E9.5 and E13.5, and the first
axons first emerge from the trigeminal ganglion at E9.5. The number of
neurons peaks between E12 and E14 and decreases by 50% to reach a
stable number by birth as a result of neuronal apoptosis that peaks at
E14. We therefore studied the development of trigeminal neurons during
the key early stages between E11 and E14 when most neurons are
differentiating from progenitor cells and extending axons to their
targets.
View larger version (130K):
[in this window]
[in a new window]
|
Figure 1.
Photomicrographs of E11 trigeminal ganglion
cultures showing the typical morphology of immature (a,
b) and mature (c) early sensory
neurons. The paired immunofluorescence (a) and
phase-contrast (b) photomicrographs demonstrate
that cells identified as immature neurons are stained with
anti-neurofilament antiserum (Wright et al., 1992). Scale bar, 50 µm.
|
|
We observed that the proportion of immature neurons in dissociated
cultures of early trigeminal ganglia from
bcl-2/ embryos was consistently
higher than the proportion of immature neurons in cultures established
from wild-type embryos of the same age (Fig.
2). In cultures established from
trigeminal ganglia at E11 and E12 when many neurons are differentiating
from progenitor cells and extending axons toward their targets in
vivo (Davies and Lumsden, 1984; Wilkinson et al., 1996), the
proportion of immature neurons was highest in cultures established from
bcl-2/ embryos at all time intervals
examined (24, 48, and 72 hr). Furthermore, the proportion of immature
neurons in cultures established from bcl-2+/ embryos was intermediate
between that in cultures established from
bcl-2/ and wild-type embryos,
suggesting a gene dosage effect. Similar results were obtained in E11
and E12 cultures of nodose ganglion neurons (data not shown).
View larger version (27K):
[in this window]
[in a new window]
|
Figure 2.
Bar charts showing the percentage of neurons that
are immature in dissociated cultures of E11 and E12 trigeminal ganglia
from bcl-2/ and wild-type embryos
after 24, 48, and 72 hr. The means + SE of the results of cultures
established from 13 bcl-2/, 26 bcl-2+/, and 14 bcl-2+/+ embryos at E11 and 17 bcl-2/, 29 bcl-2+/, and 18 bcl-2+/+ embryos at E12 are
shown.
|
|
An elevated number of immature neurons in dissociated cultures of early
sensory ganglia from bcl-2/ embryos
could be attributable to a delay in the maturation of Bcl-2-deficient
neurons, to differences in progenitor cell differentiation, or to
differences in neuronal survival in these cultures. To directly address
the question of whether Bcl-2-deficient early sensory neurons mature
more slowly than wild-type neurons, we defined cohorts of immature
neurons in cultures of E11 and E12 trigeminal neurons 18 hr after
plating and followed the fate of each neuron in these cohorts for up to
3 d in culture (Fig. 3). These
studies showed that Bcl-2-deficient neurons retain an immature
morphology much longer than wild-type neurons; the maturation of
Bcl-2-deficient neurons was delayed by 18-24 hr compared with
wild-type neurons. These marked differences in the rate of neuronal
maturation cannot be attributed to differences in the survival of
Bcl-2-deficient and wild-type neurons, because very few neurons died in
these cohorts throughout the period studied (Fig. 3). Because all data were obtained before the genotypes were ascertained, these data were
not influenced by observer bias.
View larger version (20K):
[in this window]
[in a new window]
|
Figure 3.
Graphs summarizing the results of neuron cohort
experiments comparing the maturation and survival of trigeminal neurons
from wild-type and bcl-2/ embryos
at E11 and E12. Cohorts of immature neurons were defined 18 hr after
plating, and the number of immature neurons remaining in these cohorts
(top graphs) and the number of neurons surviving in
these cohorts (bottom graphs) are expressed as
percentages of the initial cohort size at intervals up to 72 hr. The
means ± SE of the results of cultures established from 24 bcl-2/ and 23 bcl-2+/+ embryos at E11 and 22 bcl-2/ and 17 bcl-2+/+ embryos at E12 are shown.
The initial cohort size in each culture ranged from 20 to 60 neurons.
|
|
Development of early trigeminal neurons in vivo
To determine whether neuronal maturation is delayed in the
trigeminal ganglia of bcl-2/ embryos
in vivo, we counted the morphologically recognizable mature
neurons in the trigeminal ganglia of wild-type and
bcl-2/ embryos at several
developmental stages. Neurogenesis in the mouse trigeminal ganglion and
the recruitment of axons to the trigeminal nerve occur between E9.5 and
E13.5 (Davies and Lumsden, 1984; Wilkinson et al., 1996). We began
comparing the trigeminal ganglia of wild-type and
bcl-2/ embryos at E12 because large
numbers of neurons become distinguishable by morphological criteria
from other cell types at this stage (Davies and Lumsden, 1984). Because
of their small size, immature neurons cannot be distinguished from
progenitor cells and glial cells in cresyl fast violet-stained sections
and are therefore not included in these counts. Figure
4 shows that there are significantly greater numbers of morphologically distinct neurons in the trigeminal ganglia of wild-type embryos at both E12 (p = 0.0008; n = 17, t test) and E13
(p < 0.006; n = 18, t test). By E14, however, the number of neurons of the
trigeminal ganglia of bcl-2/ embryos
and wild-type embryos was not significantly different (p > 0.1; n = 22, t
test). Because all data were obtained before the genotypes were
ascertained, these data are not influenced by observer bias.
View larger version (28K):
[in this window]
[in a new window]
|
Figure 4.
Graph of the numbers of morphologically
recognizable neurons in cresyl violet-stained sections of the
trigeminal ganglia of wild-type and
bcl-2/ embryos at E12, E13, and
E14 in the trigeminal ganglia of wild-type and
bcl-2/ embryos at E12, and bar
chart of the numbers of neurons positively identified by neurofilament
staining in the trigeminal ganglia of wild-type and
bcl-2/ embryos at E12. The
means ± SE are shown (n = 53 embryos for
mature neurons; n = 11 embryos for
neurofilament-positive cells).
|
|
To ascertain whether the reduced number of morphologically identifiable
neurons in the early trigeminal ganglia of
bcl-2/ embryos was attributable to a
reduction in the number of neurons in the ganglion, we positively
identified all neurons (mature and immature) in the trigeminal ganglion
at E12 using neurofilament staining (Fig.
5). Estimates of neurofilament-positive
cells in the ganglia of wild-type and
bcl-2/ embryos revealed no
significant difference at this stage (Fig. 4). These observations
suggest that the reduction in morphologically recognizable neurons in
the trigeminal ganglia of bcl-2/
embryos during the early stages of ganglion formation is not attributable to a reduction in neurons in the ganglion. These in
vivo observations are consistent with the results of our in vitro studies that suggest that Bcl-2-deficient neurons retain an
immature morphology longer in vivo than wild-type
neurons.
View larger version (127K):
[in this window]
[in a new window]
|
Figure 5.
Photomicrograph of a section of the trigeminal of
an E12 bcl-2/ embryo stained for
neurofilament protein. Scale bar, 100 µm.
|
|
Quantification of trkA and p75 mRNAs
To determine whether the delayed morphological maturation of early
sensory neurons in bcl-2/ embryos is
a feature of a general delay in the program of development of these
neurons, we used competitive RT-PCR to quantify the level of mRNAs
encoding the NGF receptors trkA and p75. TrkA is a receptor tyrosine
kinase that is essential for the survival response of neurons to NGF
(Kaplan et al., 1991; Klein et al., 1991; Allsopp et al., 1993a),
whereas p75 has several functions (Bothwell, 1995; Davies, 1997)
including enhancing the survival response of trigeminal neurons to NGF
(Davies et al., 1993). The levels of these mRNAs are known to increase
rapidly during the early stages of trigeminal ganglion development and
are expressed predominantly if not exclusively in the neurons of the
ganglion in the embryo (Wyatt et al., 1990; Wyatt and Davies, 1993;
Davies et al., 1995). Figure 6 shows that the levels of both mRNAs increased to the same extent in the trigeminal ganglia of wild-type and bcl-2/
embryos between E12 and E14.
View larger version (13K):
[in this window]
[in a new window]
|
Figure 6.
Graphs of the levels of trkA and p75 mRNA in the
trigeminal ganglia of wild-type and
bcl-2/ embryos at E12, E13, and
E14. The means ± SE are shown (n = 42 embryos).
|
|
| |
DISCUSSION |
We have obtained compelling evidence for a novel role for Bcl-2
during the early stages of neuronal development that is distinct from
its well recognized antiapoptotic function. Newly differentiated sensory neurons initially have small, spindle-shaped, phase-dark cell
bodies that subsequently enlarge, becoming spherical and phase-bright.
By tracking the morphology of individual neurons at intervals in
cultures established from the early trigeminal ganglia of
bcl-2/ and wild-type embryos, we have
demonstrated that this clearly recognizable morphological change is
markedly delayed in Bcl-2-deficient neurons. This delay is not a
consequence of a decrease in the viability of Bcl-2-deficient neurons,
because early trigeminal neurons of
bcl-2/ and wild-type embryos survive
equally well in vitro. Thus, the absence of Bcl-2 has a
marked effect on the in vitro development of early sensory
neurons that is unrelated to its role in regulating cell survival.
Interestingly, later in development during the peak period of naturally
occurring neuronal death, Bcl-2-deficient trigeminal neurons do die
more rapidly than wild-type neurons in NGF-supplemented medium. This
decrease in the in vitro viability of older embryonic
Bcl-2-deficient trigeminal neurons is correlated with an increase in
the number of dying neurons in the trigeminal ganglion at this stage
in vivo and a reduction in the number of neurons in the
ganglion before birth (Piñón et al., 1997). Reductions in
the number of neurons in dorsal root and sympathetic ganglia and in
motoneuron populations have also been reported in
bcl-2/ mice postnatally (Michaelidis
et al., 1996).
Our in vitro observations of the delay in the morphological
maturation of early Bcl-2-deficient sensory neurons were supported by
an in vivo analysis of the trigeminal ganglia of
bcl-2/ and wild-type embryos. In
cresyl fast violet-stained sections, there were fewer morphologically
recognizable neurons in the trigeminal ganglia of
bcl-2/ embryos compared with
wild-type embryos at E12 and E13, the stage when many neurons are
differentiating from progenitor cells and starting to extend axons to
their targets (Davies and Lumsden, 1984; Davies, 1987). Because of
their small size, immature neurons are not distinguishable from
progenitor cells and other non-neuronal cells in this histological
analysis. The total neuronal complement of the trigeminal ganglion of
bcl-2/ embryos was, however, normal
during this period of development, as revealed by counting the
neurofilament-positive cells in the trigeminal ganglia of
bcl-2/ and wild-type embryos. The
most parsimonious explanation for these findings is that as in
vitro, the morphological maturation of early sensory neurons is
delayed in vivo in the absence of Bcl-2.
Of particular interest is our demonstration that the delay in the
morphological maturation of early Bcl-2-deficient neurons is not a
consequence of a general retardation of the development of
bcl-2/ embryos or of sensory neurons
within these embryos. There was no apparent difference in the
stage-specific external features (Theiler, 1972) of
bcl-2/ and wild-type embryos in each
litter, and the time course and level of expression of p75 and trkA
mRNAs were virtually identical in embryos of both genotypes. Because
these mRNAs are expressed predominantly if not exclusively in the
neurons of the embryonic trigeminal ganglion, and their levels increase
markedly with the acquisition of the NGF survival response (Wyatt et
al., 1990; Wyatt and Davies, 1993), these findings also reinforce our
evidence based on estimates of the number of neurofilament-positive
cells that the neuronal complement of the early trigeminal ganglion is
similar in bcl-2/ and wild-type
embryos.
Several studies of the consequences of manipulating the expression of
Bcl-2 in various cell lines and neurons have raised the possibility
that Bcl-2 may have functions in addition to its well known
antiapoptotic role. The differentiation of the PC12 pheochromocytoma
cell line into neurons is enhanced by overexpressing Bcl-2. However,
this effect is only observed when the cells are grown in serum-free
medium (Batistatou et al., 1993). Midbrain-derived dopaminergic cell
lines stably expressing Bcl-2 extend longer neurites than
control-transfected cells but do not have increased expression of many
neuron-specific proteins (Oh et al., 1996). Bcl-2 overexpression in a
neural crest-derived cell line enhances the outgrowth of neurite-like
processes and also increases the expression of neuron-specific enolase
(Zhang et al., 1996). Several observations indicate that the level of
Bcl-2 expression in mouse retinal ganglion cells (RGCs) influences the
ability of their axons to regenerate into co-cultured tectal explants
(Chen et al., 1997). At early fetal stages, RGCs normally express high levels of Bcl-2 and are able to extend axons into co-cultured tectal
tissue of the same age, whereas late fetal RGCs express low levels of
Bcl-2 and are not able to grow axons into tectal tissue. The ability of
early fetal RGCs to regenerate into tectal tissue is substantially
reduced in retinal explants obtained from bcl-2/ embryos, whereas late fetal
and adult RGCs from transgenic mice overexpressing Bcl-2 in neurons are
able to regenerate into tectal tissue. Recently, Bcl-2 expression has
been shown to influence axonal growth rate during development. Early
sensory neurons from bcl-2/ mouse
embryos extend axons more slowly in vitro than neurons from
wild-type embryos of the same age (Hilton et al., 1997).
In summary, we have demonstrated a novel role for endogenously
expressed Bcl-2 in sensory neurons shortly after they differentiate from progenitor cells. At this stage of development, Bcl-2 promotes an
early morphological change in the neurons but does not influence certain other aspects of their development, such as the time course of
NGF receptor expression. This action of Bcl-2 is unrelated to its well
characterized antiapoptotic role and may provide an explanation for the
widespread expression of Bcl-2 in embryonic nervous system during the
earliest stages of neuronal development (Abe et al., 1993; Merry et
al., 1994), whereas abnormal degeneration of neurons in Bcl-2-deficient
mice is not observed until the late fetal and postnatal periods
(Michaelidis et al., 1996; Piñón et al., 1997).
| |
FOOTNOTES |
Received Sept. 8, 1997; revised Feb. 5, 1998; accepted Feb. 10, 1998.
This work was supported by grants from the Cancer Research Campaign and
the Wellcome Trust. We thank Dennis Loh for the bcl-2 mutant mice, Debbie Hughes for assistance with genotyping, and Gene
Burton and John Winslow for the purified recombinant BDNF and NGF.
Correspondence should be addressed to Dr. Alun Davies at the above
address.
| |
REFERENCES |
-
Abe DS,
Harada N,
Yamada K,
Tanaka R
(1993)
Bcl-2 gene is highly expressed during neurogenesis in the central nervous system.
Biochem Biophys Res Commun
191:915-921[Web of Science][Medline].
-
Allsopp TE,
Robinson M,
Wyatt S,
Davies AM
(1993a)
Ectopic trkA expression mediates a NGF survival response in NGF-independent sensory neurons but not in parasympathetic neurons.
J Cell Biol
123:1555-1566[Abstract/Free Full Text].
-
Allsopp TE,
Wyatt S,
Paterson HF,
Davies AM
(1993b)
The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis.
Cell
73:295-307[Web of Science][Medline].
-
Allsopp TE,
Kiselev S,
Wyatt S,
Davies AM
(1995)
Role of Bcl-2 expression in the BDNF survival response.
Eur J Neurosci
7:1266-1272[Web of Science][Medline].
-
Batistatou A,
Merry DE,
Korsmeyer SJ,
Greene LA
(1993)
Bcl-2 affects survival but not neuronal differentiation of PC12 cells.
J Neurosci
13:4422-4428[Abstract].
-
Bothwell M
(1995)
Functional interactions of neurotrophins and neurotrophin receptors.
Annu Rev Neurosci
18:223-253[Web of Science][Medline].
-
Buchman VL,
Davies AM
(1993)
Different neurotrophins are expressed and act in a developmental sequence to promote the survival of embryonic sensory neurons.
Development
118:989-1001[Abstract].
-
Chen DF,
Schneider GE,
Martinou JC,
Tonegawa S
(1997)
Bcl-2 promotes regeneration of severed axons in mammalian CNS.
Nature
385:434-439[Medline].
-
Davies AM
(1987)
The growth rate of sensory nerve fibres in the mammalian embryo.
Development
100:307-311[Abstract/Free Full Text].
-
Davies AM
(1989)
Intrinsic differences in the growth rate of early nerve fibres related to target distance.
Nature
337:553-555[Medline].
-
Davies AM
(1997)
The yin and yang of nerve growth factor.
Curr Biol
7:38-40.
-
Davies AM,
Lumsden AG
(1984)
Relation of target encounter and neuronal death to nerve growth factor responsiveness in the developing mouse trigeminal ganglion.
J Comp Neurol
223:124-137[Web of Science][Medline].
-
Davies AM,
Lumsden AG
(1986)
Fasciculation in the early mouse trigeminal nerve is not ordered in relation to the emerging pattern of whisker follicles.
J Comp Neurol
253:13-24[Web of Science][Medline].
-
Davies AM,
Lee KF,
Jaenisch R
(1993)
p75-deficient trigeminal sensory neurons have an altered response to NGF but not to other neurotrophins.
Neuron
11:565-574[Web of Science][Medline].
-
Davies AM,
Wyatt S,
Nishimura M,
Phillips H
(1995)
NGF receptor expression in sensory neurons develops normally in embryos lacking NGF.
Dev Biol
171:434-438[Web of Science][Medline].
-
Garcia I,
Martinou I,
Tsujimoto Y,
Martinou JC
(1992)
Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene.
Science
258:302-304[Abstract/Free Full Text].
-
Greenlund LJ,
Korsmeyer SJ,
Johnson EM
(1995)
Role of BCL-2 in the survival and function of developing and mature sympathetic neurons.
Neuron
15:649-661[Web of Science][Medline].
-
Hengartner MO,
Horvitz HR
(1994)
C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2.
Cell
76:665-676[Web of Science][Medline].
-
Hilton M,
Middleton G,
Davies AM
(1997)
Bcl-2 influences axonal growth rate in embryonic sensory neurons.
Curr Biol
7:798-800[Web of Science][Medline].
-
Kaplan DR,
Hempstead BL,
Martin ZD,
Chao MV,
Parada LF
(1991)
The trk proto-oncogene product: a signal transducing receptor for nerve growth factor.
Science
252:554-558[Abstract/Free Full Text].
-
Klein R,
Jing SQ,
Nanduri V,
O'Rourke E,
Barbacid M
(1991)
The trk proto-oncogene encodes a receptor for nerve growth factor.
Cell
65:189-197[Web of Science][Medline].
-
Martinou JC,
Dubois-Dauphin M,
Staple JK,
Rodriguez I,
Frankowsky H,
Missotten M,
Albertini P,
Talabot D,
Catsicas S,
Pietra C,
Huarte J
(1994)
Overexpression of bcl-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischaemia.
Neuron
13:1017-1030[Web of Science][Medline].
-
McDonnell TJ,
Deane N,
Platt FM,
Nunez G,
Jaeger U,
McKearn JP,
Korsmeyer SJ
(1989)
Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation.
Cell
57:79-88[Web of Science][Medline].
-
McDonnell TJ,
Nunez G,
Platt FM,
Hockenberry D,
London L,
McKearn JP,
Korsmeyer SJ
(1990)
Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M- and D-expressing B-cell population.
Mol Cell Biol
10:1901-1907[Abstract/Free Full Text].
-
Merry DE,
Veis DJ,
Hickey WF,
Korsmeyer SJ
(1994)
Bcl-2 protein expression is widespread in the developing nervous system and retained in the adult PNS.
Development
120:301-311[Abstract].
-
Michaelidis TM,
Sendtner M,
Cooper JD,
Airaksinen MS,
Holtmann B,
Meyer M,
Thoenen H
(1996)
Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic neurons and sensory neurons during the early postnatal development.
Neuron
17:75-89[Web of Science][Medline].
-
Nakayama K,
Nakayama K,
Negishi I,
Kuida K,
Shinkai Y,
Louie MC,
Fields LE,
Lucas PJ,
Stewart V,
Alt FW,
Loh DY
(1993)
Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice.
Science
261:1584-1588[Abstract/Free Full Text].
-
Nakayama K,
Nakayama K,
Negishi I,
Kuida K,
Sawa H,
Loh DY
(1994)
Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia.
Proc Natl Acad Sci USA
91:3700-3704[Abstract/Free Full Text].
-
Oh YJ,
Swarzenski BC,
O'Malley KL
(1996)
Overexpression of Bcl-2 in a murine dopaminergic neuronal cell line leads to neurite outgrowth.
Neurosci Lett
202:161-164[Web of Science][Medline].
-
Paul G,
Davies AM
(1995)
Trigeminal sensory neurons require extrinsic signals to switch neurotrophin dependence during the early stages of target field innervation.
Dev Biol
171:590-605[Web of Science][Medline].
-
Piñón LGP,
Minichiello L,
Klein R,
Davies AM
(1996)
Timing of neuronal death in trkA, trkB and trkC mutant embryos reveals developmental changes in sensory neuron dependence on Trk signalling.
Development
122:3255-3261[Abstract].
-
Piñón LGP,
Middleton G,
Davies AM
(1997)
Bcl-2 is required for cranial sensory neuron survival at defined stages of embryonic development.
Development
124:4173-4178[Abstract].
-
Theiler K
(1972)
In: The house mouse (development and normal stages from fertilisation to 4 weeks). Berlin: Springer.
-
Veis DJ,
Sorenson CM,
Shutter JR,
Korsmeyer SJ
(1993)
Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair.
Cell
75:229-240[Web of Science][Medline].
-
Wilkinson GA,
Fariñas I,
Backus C,
Yoshida CK,
Reichardt LF
(1996)
Neurotrophin-3 is a survival factor in vivo for early mouse trigeminal neurons.
J Neurosci
16:7661-7669[Abstract/Free Full Text].
-
Wright EM,
Vogel KS,
Davies AM
(1992)
Neurotrophic factors promote the maturation of developing sensory neurons before they become dependent on these factors for survival.
Neuron
9:139-150[Web of Science][Medline].
-
Wyatt S,
Davies AM
(1993)
Regulation of expression of mRNAs encoding the nerve growth factor receptors p75 and trkA in developing sensory neurons.
Development
119:635-648[Abstract/Free Full Text].
-
Wyatt S,
Davies AM
(1995)
Regulation of nerve growth factor receptor gene expression in sympathetic neurons during development.
J Cell Biol
130:1435-1446[Abstract/Free Full Text].
-
Wyatt S,
Shooter EM,
Davies AM
(1990)
Expression of the NGF receptor gene in sensory neurons and their cutaneous targets prior to and during innervation.
Neuron
4:421-427[Web of Science][Medline].
-
Wyatt S,
Piñón LGP,
Ernfors P,
Davies AM
(1997)
Sympathetic neuron survival and TrkA expression in NT3-deficient mouse embryos.
EMBO J
16:3115-3123[Web of Science][Medline].
-
Zhang KZ,
Westberg JA,
Holtta E,
Andersson LC
(1996)
Bcl-2 regulates neural differentiation.
Proc Natl Acad Sci USA
93:4504-4508[Abstract/Free Full Text].
Copyright © 1998 Society for Neuroscience 0270-6474/98/1893344-07$05.00/0
This article has been cited by other articles:
|
|
|
|
 
P Georges, E E Cornish, J M Provis, and M C Madigan
Muller cell expression of glutamate cycle related proteins and anti-apoptotic proteins in early human retinal development
Br J Ophthalmol,
February 1, 2006;
90(2):
223 - 228.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Yagi, D. McBurney, and W. E. Horton Jr.
Bcl-2 Positively Regulates Sox9-dependent Chondrocyte Gene Expression by Suppressing the MEK-ERK1/2 Signaling Pathway
J. Biol. Chem.,
August 26, 2005;
280(34):
30517 - 30525.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Bernier, A. Bedard, J. Vinet, M. Levesque, and A. Parent
Newly generated neurons in the amygdala and adjoining cortex of adult primates
PNAS,
August 20, 2002;
99(17):
11464 - 11469.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Middleton, M. Hamanoue, Y. Enokido, S. Wyatt, D. Pennica, E. Jaffray, R. T. Hay, and A. M. Davies
Cytokine-Induced Nuclear Factor Kappa B Activation Promotes the Survival of Developing Neurons
J. Cell Biol.,
January 24, 2000;
148(2):
325 - 332.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chierzi, E. Strettoi, M. C. Cenni, and L. Maffei
Optic Nerve Crush: Axonal Responses in Wild-Type and bcl-2 Transgenic Mice
J. Neurosci.,
October 1, 1999;
19(19):
8367 - 8376.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction
