1 Unit of Molecular Neurobiology, Department of Medical Biochemistry and
Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
2 Unit of Medical Genetics Department of Medical Biochemistry Göteborg
University, 405 30 Göteborg, Sweden
3 Institute of Child Health, University College London, London WC1N 1EH,
UK
* Author for correspondence (e-mail: patrik.ernfors{at}mbb.ki.se)
Accepted 16 April 2005
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SUMMARY |
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Key words: Mouse, Peripheral nervous system, Migration, Fkh3, Foxs1
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Introduction |
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More recently, late emigrating trunk neural crest was shown to give rise to
the BC cells of the dorsal root entry zone (DREZ) and motor exit points, which
appear morphologically in the rat at E13 and in the mouse at E10.5
(Topilko et al., 1994). Unlike
dorsal root ganglion progenitor cells that cease proliferation around E12, at
which time the programmed cell death commences in the mouse
(Lawson and Biscoe, 1979
;
Pinon et al., 1996
), the
boundary cap cells proliferate throughout embryogenesis
(Altman and Bayer, 1984
).
Despite continuous proliferation of these cells, the size of the BC decreases
from E17 onwards. Its disappearance at early postnatal stages appears not to
be correlated with increased apoptosis
(Altman and Bayer, 1984
;
Golding and Cohen, 1997
). The
BC cells express monoamine oxidase B (Maob)
(Vitalis et al., 2003
), the
zinc-finger transcription factor Krox20 (Egr2 Mouse Genome
Informatics) (Wilkinson et al.,
1989
) and the TrkB neurotrophin receptor
(Ernfors et al., 1992
). In the
chick, the late emigrating cranial neural crest cells expressing Cad7 and
Krox20 localise specifically to the cranial motor nerve exit points
(Niederlander and Lumsden,
1996
) and maintain a boundary that is permissible for axons to
grow through, but prevents neuronal migration
(Vermeren et al., 2003
). The
BC is important for sensory afferent ingrowth at the DREZ
(Golding and Cohen, 1997
).
Recently, genetic tracing of boundary cap cells using the Krox20 locus has
revealed that some trunk sensory neurons are derived from the boundary cap,
and that the boundary cap cells also contribute with satellite cells and
Schwann cells to the peripheral nervous system
(Maro et al., 2004
).
The finding that the BC contributes with glial and neuronal cells to the
peripheral nervous system suggests that they could be multipotent stem cells.
Self-renewing NCSCs isolated from the migrating neural crest or tissues
derived from it such as the sciatic nerve and the enteric nervous system in
the gut share some common traits with neural crest cells (NCCs), as the
ability to form not only neurons but also smooth muscle cells and glia
(Anderson, 1997;
Bixby et al., 2002
;
Morrison et al., 1999
;
Rao and Anderson, 1997
).
However, it is intriguing that these NCSCs differentiate only into autonomic
neurons and have never been observed to spontaneously differentiate into
sensory neurons in vitro or after transplantation in vivo
(Anderson, 2000
;
Morrison et al., 1999
;
White et al., 2001
). Both
sensory and autonomic neurons can be generated in cultures of neural tube
explants, in which sensory precursor cells constitute about 1% of the cells
and divide only during the first 2 days of culture
(Greenwood et al., 1999
).
Application of Wnt1 has been shown to direct these cells towards a sensory
lineage, as shown by the expression of the transcription factor Brn3a, a
marker for sensory precursor cells (Lee et
al., 2004
).
In this study, we identify the BC as a source of NCSCs with unique characteristics. We show that the bNCSCs express markers similar to previously isolated NCSCs, are multipotent by forming neurons, glia and smooth muscle-like cells and are able to self-renew but when differentiated spontaneously generate functional sensory neurons of several subclasses.
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Materials and methods |
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Generation of Fkh3lac-z /+ knock in mice
A 10 kb fragment from the Fkh3 locus was isolated and an
nls-lacZ cassette also containing a neomycin-resistance gene, driven
by the PGK promoter and polyA was put in frame 18 amino acids downstream of
Fkh3 start codon, replacing a 600 bp part of the Fkh3 gene.
Homologous recombined embryonic stem cell clones were injected into C57/Bl6
blastocysts to generate chimeric mice. After germline transmission, the mice
were on a 129SVxC57/Bl6 background.
Immunocytochemistry
Immunofluorescence analyses were performed using a variety of antibodies
against neuropeptides, transcription factors, receptors and neuronal filaments
(see below).
Cells were fixed in 4% PFA (Merck) at room temperature for 30 minutes, permeabilised and blocked using PBS with 0.1% Triton X-100 (Merck) [or 0.1% Tween-20 (Merck) for filament staining] and 3% BSA (Sigma) or 5% serum (Chemicon) from the same species in which the secondary antibody was generated. The cells were incubated with primary antibody overnight at 4°C. Species and isotype-specific fluorescent antibodies (donkey Cy2- or Cy3-conjugated anti-rabbit, mouse, chick or guinea pig, 1:200, Jackson) were applied for 1 hour at room temperature. The sections were rinsed four times in PBS for 15 minutes, the second wash including Hoechst 33342 (11 ng/ml, Molecular Probes). Pictures were taken using a Zeiss Axiovert 100M or Zeiss LSM 510 confocal microscope. Antibodies were as follows: ßIII-Tubulin (Tuj1, mouse, 1:250, Promega), Brn3a (mouse, 1:200, Covance), calcitonin gene-related peptide (Cgrp; Calca Mouse Genome Informatics; guinea pig, 1:200, Peninsula Labs), choline acetyltransferase (ChAT, goat, 1:100, Chemicon), glial fibrillary acidic protein (Gfap, rabbit, 1:400, DAKO), GDNF family receptor Ret (goat, 10 µg/ml, RnD systems), low affinity neurotrophin receptor p75 (p75NTR, mouse, 1:200, Chemicon), monoamine oxidase B (Maob, rabbit, 1:1000, a gift from Olivier Cases), Nestin (mouse, 1:500, Hybridomabank), peripherin (Per; Prph1 Mouse Genome Informatics; rabbit, 1:500, Chemicon), smooth muscle actin (Sma, mouse, 1:400, Sigma) and tyrosine hydroxylase (Th, rabbit, 1:5000, Diasorin).
RT-PCR
Total RNA from 20 stem cell clones, dorsal root ganglia, boundary cap and
central part of dorsal root ganglia from E11 mouse embryo were extracted using
Absolutely RNATM Nanoprep kit (Stratagene) following manufacturer's
instruction. Reverse transcription (RT) was carried out 10 minutes at 65°C
followed by 1 hour at 37°C and 15 minutes at 70°C in 20 µl
reactions containing 0.5 mM dNTP each, 10 mM DTT, 0.5 µg
oligod(T)15 (Promega) and 200 U of M-MLV-RT (Gibco BRL). For stem
cell clones, total RNA extract was reverse transcribed. For dorsal root
ganglia, boundary cap and central part, 500 ng of total RNA were reverse
transcribed. The amount of template was adjusted to equal quantity between
samples based on the level of HPRT. PCR was conducted in 25 µl reactions
containing 10% RT product, 2 µM each dNTP, 10 pmol of each primer
(MWG-Biotech AG), 3 mM MgCl2 and 0.625 U of Ampli Taq GoldTM
(Roche Molecular Systems). cDNA was denatured 10 minutes at 95°C and
amplified for 35 cycles in a two step program as following: 30 seconds at
95°C and then 30 seconds annealing and polymerisation (55°C to
65°C depending on the primers). PCR products were separated on 2% agarose
gels containing ethidium bromide. Primers were as follows: Ret
(5'-CTTGGCAGAAATGAAGCTTGTACA-3' and
5'-GTCCCTCAGCCACCAAGATGT-3'; nucleotides 2595 to 2618 and 2639 to
2659; 64 bp); Brn3a (Pou4f1 ñ Mouse Genome Informatics)
(5'-AGGCCTATTTTGCCGTACAACC-3' and
5'-CTCCTCAGTAAGTGGCAGAGAATTTCAT-3'; nucleotides 1956 to 1977 and
2081 to 2108; 152 bp); Ngn1 (Neurog1 Mouse Genome Informatics)
(5'-CCCTCGGCTTCAGAAGACTTCA-3' and
5'-CGTCGTGTGGAGCAGGTCTTT-3'; nucleotides 625 to 646 and 691 to
711; 86 bp), Ngn2 (Neurog2 ñ Mouse Genome Informatics)
(5'-TCCAACTCCACGTCCCCATACC-3' and
5'-GCTGCCAGTAGTCCACGTCTGA-3'; nucleotides 658 to 678 and 709 to
730; 72 bp); Krox20 (5'-TGGATGCCAGTTGTTCTGAGACTT-3' and
5'-GCTGTCCTCGATCAAAGGAATCA-3'; nucleotides 1972 to 1995 and 2020
to 2042; 70 bp), Otx1 (5'-GCAGCCTCCTACCCTATGTCCTAT-3' and
5'TGCAGTCTACACCGCCAAAGTA-3'; nucleotides 652 to 675 and 734 to
745; 93 bp), Pax2 (5'-AGTCTTTGAGCGTCCTTCCTATCC-3' and
5'-CATTCCCCTGTTCTGATTTGATGT-3'; nucleotides 795 to 818 and 842 to
865; 70 bp), Pax5 (5'-AACAGGATCATTCGGACAAAAGTA-3' and
5'-AGCCTGTAGACACTATGCTGTGA-3'; nucleotides 438 to 461 and 497 to
519; 81 bp).
In situ hybridisation
Embryos were collected at different stages, fixed overnight (4% PFA, in
PBS), washed in PBS, cryopreserved (30% sucrose in PBS), embedded in OCT and
sectioned at 14 µm. Before hybridisation, slides were air dried for 2-3
hours at room temperature. Full-length mouse Krox20 was used to synthesise
digoxigenin-labelled antisense riboprobe according to supplier's instructions
(Roche) and purified by LiCl precipitation. Sections were hybridised overnight
at 70°C with a solution containing 0.19 M NaCl, 10 mM Tris (pH 7.2), 5 mM
NaH2PO4*2H2O/Na2HPO4
(pH 6.8), 50 mM EDTA, 50% formamide, 10% dextran sulphate, 1 mg/ml yeast tRNA,
1xDenhardt solution and 100 to 200 ng/ml of probe. Sections were then
washed for times for 20 minutes at 65°C in 0.4xSSC pH 7.5, 50%
formamide, 0.1% Tween 20 and three times for 20 minutes at room temperature in
0.1 M maleic acid, 0.15 M NaCl and 0.1% Tween 20 (pH 7.5). Sections were
blocked 1 hour at room temperature in presence of 20% goat serum and 2%
blocking agent (Roche) prior to incubation overnight with AP-conjugated
anti-DIG-Fab-fragments (Roche, 1:2000). After extensive washing, hybridised
riboprobes were revealed by performing a NBT/BCIP reaction in 0.1 M Tris HCl
pH 9.5, 100 mM NaCl, 50 mM MgCl2 and 0.1% Tween 20.
X-Gal staining
Embryos or cells were fixed in Webster solution for 45 minutes on ice and
then stained in coloration solution [3.1 mM FeK3(CN)6,
3.1 mM FeK4(CN)6 and 0.4 mg/ml X-gal in phosphate
buffer] overnight at 37°C. Embryos or cells were then post fixed in
Webster for 48 hours at 4°C.
Calcium imaging
Ratiometric microfluorometric measurements of Ca2+
concentrations were performed using Fura-2. Clones differentiated for 5 days
or freshly isolated dissociated adult dorsal root ganglion cells were
transferred from propagation medium to Hank's balanced salt solution (HBSS;
145 mM NaCl, 5 mM KCl, 10 mM HEPES 10, 2 mM CaCl2, 1 mM
MgCl2, 10 mM D-glucose) buffered to pH 7.4 at room temperature and
containing 2 µM Fura-2 acetoxymethyl (AM) ester (derived from a stock
solution of 2 mM Fura dissolved in DMSO) and 80 µM Pluronic F-127 (both
from Molecular Probes) for 30 minutes. Coverslips were subsequently placed in
a recording chamber and viewed with 10x Fluoar objectives in a Zeiss
Axiovert 200 using DCLP 410 and LP 440 filters. Pairs of images were collected
at intervals of 1 or 2 seconds with alternating exposure of 340 and 380 nm
each for 50-200 mseconds using a Polychrome IV and an air-cooled CCD Imago
Camera (640x480 pixel resolution) that were controlled by TILLviSION 4.0
software (all from Till Photonics, Gräfeling, Germany). This software was
also used to compute ratios of fluorescent images on a pixel by pixel basis
representing changes of intracellular Ca2+ transients. Coverslips
were superfused with HBSS and drugs were applied using a gravity driven
application system with magnetic valves allowing rapid fluid exchange rates at
an uniform speed in each experiment of 2 ml/minute. We used 1 mM of the
TRPM8 agonist menthol for 10 seconds, 1 µM of the TRPV1 agonist capsaicin
(both diluted from a 10 M or 20 mM stock solution in 100% ethanol to a final
ethanol concentration of 0.01 or 0.005%, respectively) for 4 seconds, 30%
hypo-osmolar solution 30 seconds and 100 mM KCl for 4 seconds allowing a
washout of 30 or 60 seconds between each stimulus. As cold stimuli, cooled
HBSS was applied using a custom made application system in which the
temperature close to the cell as measured in the field of analysis as measured
by a thermocoupler was lowered to 8°C.
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Results |
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In addition to markers previously used to characterise NCSCs, a number of
other transcription factors and cell membrane proteins have been described in
the neural crest and sensory neurons. RT-PCR analysis showed expression of
these neural crest and sensory neuron genes in the stem cells (Ret, Brn3a,
Ngn1, Ngn2 and Krox20; Fig.
1E). Expression of Brn3a, Ngn1, Ngn2 indicates that the cells are
of the sensory lineage of the neural crest
(Eng et al., 2001;
Lin et al., 1998
;
Perez et al., 1999
;
Xin et al., 1992
). The stem
cells and the E11.5 dorsal root ganglia showed a similar expression profile.
Otx1, Pax2 and Pax5 were not expressed, showing that the cells have a
posterior and peripheral patterning.
|
We therefore examined whether Maob was expressed in our culture. As our stem cell protocol includes an enrichment step 12 hours after establishment of the culture, the percentage of Maob-expressing cells was examined before and after this step.
We found a 2.5-fold increase in the percentage of Maob+
cells at 12 hours (i.e. fold increase of Maob+ cells over total
number of cells at 12 hours compared with at 2 hours)
(Fig. 2E-G). Similar results
were obtained from cultures inhibiting cell division or transcription with
cytosine arabinoside or actinomycin D, respectively
(Fig. 2G). As there was no
significant change in the absolute number of Maob+ cells in any
condition (data not shown), we conclude that the increased proportion of
Maob+ cells is due to a loss of other cell types, rather than
induction of Maob expression or proliferation. Thus, Maob+ cells
survive and are enriched under our culture conditions.
To determine whether the BC cells could be the source of the stem cells, the BC including the dorsal edge of the ganglion (b in Fig. 2H) and the central part of the ganglion (c in Fig. 2H) was micro-dissected, dissociated and plated separately. RT-PCR for Krox20 confirmed the technique of micro-dissecting the BC. Krox20 mRNA was detected in the BC sample but never in the tissue from the central part of the ganglion (Fig. 2I; n=3 dissections). The central part of the dorsal root ganglion was found to contain very few clone-forming stem cells, whereas a significantly higher number of clones formed from the BC at all time points measured (Fig. 2J). Combined, the above results show that the clone forming cells are derived from the BC.
Boundary cap NCSCs (bNCSCs) self-renew and are multipotent
The difference between stem and progenitor cells is the ability of stem
cells to self-renew and in the neural crest to give rise to progenies of both
neuronal and non-neuronal cell types, including neurons, glia and smooth
muscle-like myofibroblasts (Gage,
1998; Shah et al.,
1996
). Clonal experiments were performed to examine whether
individual BC cells were giving rise to all three lineages. Cells were plated
at a density well below the previously reported limit for clonal expansion (50
cells/cm2) and each cell was individually marked and followed over
time to exclude contamination from neighbouring cells
(Nunes et al., 2003
). Cell
clusters arising from such cultures were individually transferred into single
wells. The clones were differentiated and stained for ßIII-tubulin, Gfap
and smooth muscle actin (SMA) for identification of neuronal, glia and smooth
muscle-like cells (Morrison et al.,
1999
). Out of 60 clones analysed, all contained SMA+
cells, 88.3% also gave rise to neurons and glia. 8.3% of the clones gave rise
to only glia and SMA+ cells, 1.7% neurons and SMA+ cells
and 1.7% SMA+ cells only. When we performed repeated subcloning
(two additional passages of single cell clones), all out of 127 clones
retained the capability of producing both neurons and glia. Thus, the BC
neural crest cells are multipotent stem cells.
bNCSCs differentiate into peripheral sensory neurons
To examine if the bNCSCs can differentiate to peripheral neurons, we
analysed expression of peripherin, which is a type III intermediate filament
expressed in most, but not all, sensory and sympathetic neurons in vivo
(Troy et al., 1990). After 5
days in vitro under differentiating conditions, neurons expressing both
peripherin and ßIII tubulin had long neurites, stretching sometimes
throughout the extent of the culture dish
(Fig. 3A). The morphology of
the cell soma and neuritic processes of the
peripherin+/ßIII-tubulin+ cells resembled that of
cultured primary E11.5 dorsal root ganglion neurons (data not shown). In
addition to peripherin+/ßIII-tubulin+ neurons,
another peripherin-/ßIII-tubulin+ population was
identified (Fig. 3A). In
contrast to peripherin, ßIII-tubulin also marks early, not fully
differentiated neurons (Moody et al.,
1989
). Even after 2 weeks of differentiation, these
peripherin-/ßIII-tubulin+ neurons failed to express
any mature neuronal marker (data not shown). The proportion of such cells
increased upon multiple passages of the bNCSCs. This property of the bNCSCs is
markedly different from the autonomic NCSCs that differentiate independently
of cellular cues (Morrison et al.,
1999
).
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We also used Ca2+ imaging studies to determine whether bNCSCs develop into a functionally homogenous progeny or whether individual bNCSCs could give rise to heterogeneous offspring. Using the functional test described above, we found that 72% of the clones generated neurons belonging to two or more subtypes. This means that a single bNCSC can give rise to multiple functional subclasses of sensory neurons (Fig. 7) and strongly suggests that the stem cells in the BC have not yet undergone a restriction towards a specific sensory neuronal modality.
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Discussion |
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bNCSCs are specified to the sensory lineage
Specification and commitment of cell lineages are defined experimentally
(Baker and Bronner-Fraser,
2001). A cell lineage is specified to follow a specific pathway if
it does so when cultured in a neutral medium in the absence of any instructive
signals. A lineage of cells is committed to a pathway of differentiation if
they do so regardless of their environment, thus, even in the presence of
instructive signals for another cell fate. Specification is best determined in
cell culture. Although commitment can be addressed in culture by challenging
with different instructive signals, it is best addressed by cell grafting into
an ectopic environment of the embryo. A number of instructive signals acting
on the neural crest have been identified. BMP potently induces neurogenesis
and instructs an autonomic fate in cultured NCCs and NCSCs
(Morrison et al., 1999
).
Although freshly isolated NCCs have the potential to differentiate into
sensory neurons following transplantation in the chick or after one passage in
culture in the presence of Wnt1/ß-catenin signal [shown by the presence
of Brn3a-immunoreactivity (Lee et al.,
2004
)], NCCs passaged more than once fail to do so
(White et al., 2001
).
Furthermore, NCSCs with the ability to self-renew for several passages in
culture, fail to differentiate to sensory neurons in vitro even under forced
over expression of neurogenins (Lo et al.,
2002
). We found that the bNCSCs failed to differentiate into
autonomic neurons even when challenged with instructive autonomic signals.
However, our culture conditions are different from those used in previous
studies of sciatic nerve-derived neural crest stem cells (sNCSCs)
(Morrison et al., 1999
;
Shah et al., 1996
;
Stemple and Anderson, 1992
).
To test whether the bNCSCs display a different potential when compared with
sNCSCs, we compared both NCSC types under identical culture conditions. BMP
did not induce any autonomic neurons in any of the stem cells, indicating that
our culture conditions are not permissible for the differentiation of
Th-positive autonomic neurons. By contrast, BMP potently increased
neurogenesis of both bNCSCs and the sNCSCs, indicating that it acts
instructively on multipotent progenitor cells to differentiate into neurons,
as reported previously (Morrison et al.,
1999
). As sNCSCs did not differentiate into sensory neurons, we
conclude that it is not the defined culture condition used in our study that
is instructive towards a sensory fate. Thus, our results show that, unlike
sNCSCs, the bNCSCs are specified to differentiate into the sensory lineage.
However, it remains to be established whether the bNCSCs are not only
specified but also committed to the sensory lineage.
A common progenitor in the BC for nociceptive and thermoreceptive sensory neurons
An important principle distinction of adult dorsal root ganglion neurons is
their division into large- and small-diameter neurons. Within each category,
there are many functional phenotypes that subserve such diverse functions as
proprioception and touch or pain, itch and thermoreception. The timing and
instructive signals determining cell fate between the functional subtypes has
remained largely elusive. Because large mechanoreceptive neurons populate the
dorsal root ganglion prior to the appearance of small nociceptive neurons, the
early arriving mechanoreceptive neurons could provide an instructive scaffold
for the later arriving nociceptive neuron progenitor cells
(Anderson, 2000). This
hypothesis implies that the restriction between different functional types of
sensory neurons takes place within the dorsal root ganglion, similar to that
described for motoneurons, where the birth of new motoneuron subsets occur in
a feed-forward mechanism (Sockanathan and
Jessell, 1998
; Sockanathan et
al., 2003
). However, BC cells appear to be among the last cells
generated by the neural crest, which would exclude them as scaffolding forming
early arriving cells. Expression of sensory lineage transcription factors
Ngn1, Ngn2 and Brn3a (Fedtsova and Turner,
1995
; Ma et al.,
1999
) already in the pre-migratory or migratory neural crest
argues for a restriction between sensory and autonomic lineages in the
migratory neural crest. In agreement, forced expression of Ngn2 in the
migrating crest cells in the chick biases these cells to a sensory fate
(Perez et al., 1999
).
Consistently, expression of Ngn2 biases the cells towards the sensory lineage
also in the mouse (Zirlinger et al.,
2002
). Thus, cell-intrinsic differences of migrating neural crest
cells together with environmental cues determine cell fate. The instructive
signals imposed onto the neural crest populating the dorsal root ganglion
during migration or after condensing into a ganglion appear not to fate the
stem cells in the BC, as the bNCSCs can generate both nociceptive and
thermoreceptive sensory neurons and possibly most or all other types of
sensory neurons, as well as glia and smooth muscle cells. This is consistent
with the fate of the boundary cap cells, which have been shown to have the
potential to generate nociceptive, mechanoreceptive and possibly other
neuronal subtypes in vivo, in addition to glia
(Maro et al., 2004
). By
contrast, while generating large quantities of autonomic neurons in vitro,
sNCSCs have not been reported to generate anything else than Schwann cells and
endoneurial fibroblasts in vivo (Joseph et
al., 2004
).
Concluding remarks
Dorsal root ganglion neurons are generated from the neural crest shortly
after their delamination from the dorsal neural tube, with the cervical
ganglia condensing around E9.5. The contribution of this early population of
migrating neural crest to most of the dorsal root ganglion neurons has been
firmly established in several species, including the mouse. In both the avian
and the rodent, the wave of neural crest cells forming the dorsal root
ganglion is separated in time from that which populates the BC, probably
spaced by neural crest cells migrating dorsolaterally that belong to the
melanocyte lineage (Le Douarin et al.,
1992; Serbedzija et al.,
1989
; Serbedzija et al.,
1990
; Topilko et al.,
1994
). Thus, the BC cells clearly belong to a different lineage of
cells than the early neural crest cells that generates the dorsal root
ganglion. We show that the bNCSCs self-renew and can generate neurons, glia
and smooth muscle-like cells. Our data suggest that the developmental programs
in the dorsal root ganglion, including specification of different neuronal
subtypes, cell cycle exit and programmed cell death are not imposed upon the
BC stem cells. Our findings raise a number of important issues such as the
nature of the refractory mechanism by which the BC stem cells escape the
developmental programs imposed upon the rest of the neural crest, the
evolutionary origin and the biological role of this unique population of stem
cells.
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ACKNOWLEDGMENTS |
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