1 Department of Anatomy and Cell Biology, University of Melbourne, Melbourne,
Victoria 3010, Australia
2 UMR 955 INRA de Genetique Moleculaire et Cellulaire, Ecole Nationale
Veterinaire d'Alfort, Maisons-Alfort Cedex, France
* Author for correspondence (e-mail: m.murphy{at}unimelb.edu.au)
Accepted 14 October 2004
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SUMMARY |
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Key words: Neural crest, Melanocyte, Specification, Lineage segregation, Precursors, Stem cells, Neural tube
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Introduction |
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A number of experimental approaches have been used to address the question
of when and where cell fate decision is made in the NC. The classic
experiments from Le Douarin and co-workers employed grafting of neural
primordium between quail and chicken (Le
Douarin and Kalcheim, 1999), and tracing the quail NC cells
throughout the embryo. Cells derived from any region of the NT could generate
most NC derivatives, supporting the idea that fate is decided where the cells
migrate. However, certain restrictions in developmental potential applied; for
example, trunk NC was unable to give rise to the mesenchymal derivatives of
the head.
In vitro studies have followed the progeny of single NC cells in clones
(Le Douarin and Kalcheim,
1999). Some studies find a very heterogeneous mixture of clones,
including some with many different NC cell types, and have been interpreted to
support the existence of multipotential NC cells that become progressively
fate restricted (Dupin et al.,
1998
; Sieber-Blum and Cohen,
1980
; Stemple and Anderson,
1992
). Other studies find that almost half the clones are of a
single phenotype and support an argument for distinct NC lineages that diverge
before or soon after crest cells emerge from the neural tube
(Henion and Weston, 1997
;
Luo et al., 2003
). Where these
studies may reveal the potential of NC cells under different environmental
conditions in vitro, this may be different from the normal developmental fate
of the cell in vivo, termed specification
(Dorsky et al., 2000
).
The fates of individual dorsal NT cells have also been followed in vivo.
Individual cells gave rise to one, two or more different NC cell types, as
well as to NT cells, which suggests there is a considerable heterogeneity
within NC cells as they emerge from the NT, with some cells multipotential and
others committed to a particular fate (Le
Douarin and Kalcheim, 1999). These studies were generally similar
through tetrapods (Bronner-Fraser and
Fraser, 1989
; Bronner-Fraser
and Fraser, 1988
; Collazo et
al., 1993
; Frank and Sanes,
1991
; Serbedzija et al.,
1994
). The exception is the zebrafish, a teleost, where similar
experiments showed that most NC cells differentiated into only one cell type
(Raible and Eisen, 1994
;
Schilling and Kimmel, 1994
).
Whether this difference is related to the marked differences between teleost
and tetrapod neurulation and NC development is unknown.
For melanocytes, in vitro clonal analyses provide evidence for the
progressive restriction of cell fate from a multipotent NC stem cell to a
glial-melanocyte progenitor, then a melanocyte
(Dupin and Le Douarin, 2003).
Alternatively, there is mounting evidence that melanocytes are specified very
early. We showed that a subpopulation of trunk NC cells begin to express the
receptor tyrosine kinase Kit (previously known as c-kit), early in culture,
and are dependent on Kit signaling for survival and proliferation
(Murphy et al., 1992
;
Reid et al., 1995
;
Reid et al., 1996
). These
Kit+ cells only give rise to melanocytes and thus represent
melanocyte progenitor cells (Luo et al.,
2003
; Reid et al.,
1995
). Studies in vivo have traced the expression of other
melanocyte markers, and determined that these markers are expressed soon after
emigration from the NT (Kitamura et al.,
1992
; Reedy et al.,
1998a
; Wehrle-Haller and
Weston, 1995
). Studies in aves provide evidence that
dorsolaterally migrating NC cells are already specified to the melanocyte
lineage (Reedy et al.,
1998a
).
Thus, for tetrapods, different experiments point both to multipotentiality
and early specification, and it is still unclear where, when and how NC
specification occurs. The use of markers that distinguish different NC
lineages might help to clarify this issue. These markers could be used to look
for evidence of specification within the NT, and if it does occur, when and
where it happens. We have investigated Kit and the neurotrophin receptor p75
(Mujtaba et al., 1998;
Stemple and Anderson, 1992
) as
potential markers for different NC precursors within the NT.
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Materials and methods |
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For immunohistochemistry, embryos were fixed in either 2% PFA for 30 minutes or 4% PFA for 2-4 hours, then embedded in OCT compound (Sakura, Tokyo, Japan) and immunohistochemistry performed on 20 µM cryostat sections. Sections from embryos fixed in 2% PFA were incubated with mouse anti-ßgal (1:1000, Promega, Annandale, Australia) and either rabbit anti-Trp2 (1:1000) or rabbit anti-p75 (1:100, Promega); or with mouse anti-Isl1 (1:1000; Developmental Studies Hybridoma Bank, Iowa City, IA) and rabbit anti-ßgal (1:5000; Cappel, Seven Hills, Australia). Antibodies were diluted in Casblock (Zymed, San Francisco, CA). Sections from embryos fixed in 4% PFA were incubated with rabbit anti-ßgal (as above), and with rat antibodies to CD31 (1:1000, Serotec, Oxford, UK), CD34, (1:1000, BD Pharmingen, Singapore), CD45 (1:500, BD Pharmingen), F4/80 (1:500, Serotec) or, alternatively, with rat anti-mouse p75 (1:100, Chemicon, Temecula, CA). Sections incubated with mouse anti-ßgal were washed and incubated in biotinylated anti-mouse IgG (1:400 in Casblock; Vector, Burlingame, CA). All sections were washed in 0.1% Triton X-100 and incubated with appropriate Alexa fluorophore labelled reagents (Molecular Probes, Eugene, OR). After antibody incubations, sections were washed in PBS and coverslipped in fluorescent mounting medium (DAKO, Carpinteria, CA). Sections were imaged on a Bio-Rad laser scanning confocal microscope. Images were processed with Adobe Photoshop 5.5.
For ßgal histochemistry combined with p75 immunohistochemistry of whole-mount embryos, embryos were stained for ßgal as above for 8 hours on a rotating shaker at 75 rpm, the ventral tissue was dissected away and immunohistochemistry performed with rabbit anti-p75 for 48 hours at room temperature at 75 rpm. Embryos were flat mounted on clean glass slides, dorsal side up, and coverslipped with fluorescent mounting medium. Overlapping brightfield images were taken using a 10 x objective on an Olympus BX61 microscope and merged in Photoshop Elements 2. For imaging the double labelling, brightfield images were taken, inverted, false coloured red, and fluorescent images were taken at the same focal plane. Both images were deconvolved using No Neighbours algorithm and merged using AnalySIS software (Soft Imaging Systems).
Genotyping
Genomic DNA was solubilized from yolk sacs by digestion with proteinase K
(Sambrook et al., 1989). DNA
was genotyped for the three Kit genotypes using two pairs of
oligonucleotides:
PCR reactions (20 µl) were carried out in the presence of 1.5 mM MgCl2, 1xPCR Enhance (Invitrogen, Carlsbad, California) and Taq DNA polymerase (Bioscientific, Sydney, Australia), and the reaction conditions were: 94°C for 7 minutes; followed by 30 cycles of 94°C for 30 seconds, 57°C for 30 seconds and 72°C for 30 seconds. The amplified fragment size for the lacZ oligonucleotide pair was 800 bp, and the Kit oligonucleotide pair amplified a 148 bp fragment.
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Results |
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p75 staining reveals an NC precursor population that is distinct from the Kit+ cells on the dorsal midline of the NT
The low affinity neurotrophin receptor, p75, has been used to identify
putative NC stem cells and, in particular, to distinguish them from CNS
progenitor cells (Mujtaba et al.,
1998; Stemple and Anderson,
1992
). To look for such NC cells, we stained whole-mount embryos
and sections of WlacZ/+ embryos with p75 antibodies. At
E9.0 in the trunk, p75 staining was present in areas of NC migration, and
predominantly in areas of most ventral migration; staining extended along most
of the trunk but there were only few cells in caudal regions
(Fig. 5; n=4). There
was also strong staining in ventral and lateral regions of the NT, but almost
no staining on the dorsal midline. By E9.5, staining was still present in the
periphery, but there was also significant staining along the dorsal midline of
the NT, which extended down the trunk but not to its most caudal extent
(Fig. 5; n=4). The p75
staining in the periphery at these ages most likely represents ventrally
migrating NC cells, and the staining that appears on the dorsal midline of the
NT by E9.5 represents premigratory NC cells. A similar pattern of staining was
observed at E10.5-E11, and at these ages the staining along the dorsal midline
extended along the entire length of the trunk
(Fig. 5; n=4 for both
E10.5 and E11). In addition, the pattern of p75 staining was more complex at
these ages and other cells were positive
(von Schack et al., 2001
).
|
By E11, many ßgal+ cells were present in the ectoderm (Figs 2, 5). In cervical and midtrunk regions, these cells were dispersed away from the midline, whereas in the lower trunk many ßgal+ cells were near the midline. p75 began to be expressed extensively in the ectoderm at this age and the fraction of cells that stained for both ßgal and p75 was difficult to determine. Nevertheless, in areas of the ectoderm where it could be determined, the ßgal+ cells did stain for p75 (not shown), suggesting that these cells express p75 during migration into the ectoderm. By contrast, in areas of ventral NC migration, none of the p75+ cells were ßgal+ (Fig. 5; 185 cells counted). This is consistent with our findings that Kit is only expressed by melanocyte progenitors that migrate into the ectoderm.
The combination of ßgal and p75 staining reveals distinct populations of NC cells within the NT: (1) the Kit+ population, present from E9, in greatest numbers in cervical regions of the trunk, constitutes the melanocyte progenitor population; (2) the p75+/Kit population, present from E9.5, extends throughout the trunk region and migrates ventrally; and (3) an early population of cells which must also be present is the p75/Kit, which migrates prior to E9.5, and contributes to the ventrally migrating p75+ cells.
Kit+ cells on the dorsal midline at the midbrain-hindbrain junction are melanocyte progenitor cells
In contrast to the trunk, dorsal midline expression of ßgal in the
head was focal and restricted to the midbrain-hindbrain junction
(Fig. 6A,B; n=15).
There was also strong expression of ßgal in ventral regions of the
midbrain-hindbrain junction (Fig.
6A,B). Soon after their appearance on the dorsal midline from
E9.5-10, ßgal+ cells appeared associated with the ectoderm, in
a region both lateral and caudal to the midbrain-hindbrain junction
(n=19, Fig. 6A,C). As
development proceeded, these ßgal+ cells progressively
occupied more distal regions of the ectoderm (compare
Fig. 6A, at E10.5, with 6C,D,
at E11). In addition, a stream of ßgal+ cells appeared,
starting at the midbrain-hindbrain junction and extending caudally and
laterally through the mesenchyme adjacent to the hindbrain
(Fig. 6A,C,D). The
ßgal+ cells, both in the ectoderm and in the stream in the
mesenchyme, expressed Trp2 (Fig.
6E), indicating that they are melanocyte progenitor cells. This
pattern of expression, first at the midbrain-hindbrain junction, then in the
ectoderm and mesenchyme, is consistent with emigration of Kit+
melanocyte progenitors from the dorsal midline of the NT at a specific region
in the developing head.
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Discussion |
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Our findings also indicate that the migrated NC Kit+ cells only
give rise to melanocytes. The Kit+ cells that migrate into the
ectoderm all express Trp2, indicating that they are melanocyte progenitors. We
looked for any evidence that these cells may give rise to other NC cell types.
None of the ventrally migrating p75+ NC cells express Kit. We did
find Kit+ cells in regions of ventral migration, but these cells
were contained within blood vessels, indicating that they were not NC derived.
More studies, such as studies involving the generation of a Kit
tamoxifen-inducible cre line of mice, could further clarify this issue. In
vitro, Kit+ NC cells only develop into melanocytes
(Luo et al., 2003;
Reid et al., 1995
). Even in
conditions that favor neuronal development, there was no evidence that
Kit+ cells ever gave rise to anything but melanocytes
(Reid et al., 1995
).
Elimination of Kit signaling results in the death of the Kit+ cells
as soon as they migrate from the NT, and a resultant total loss of skin
melanocytes (Bernex et al.,
1996
; Reid et al.,
1995
; Wehrle-Haller and
Weston, 1995
; Yoshida et al.,
1996
). Thus, Kit+ cells have a restricted cell fate in
vivo and are progenitors for all skin melanocytes. These findings are
consistent with other studies that suggest that melanocyte progenitors are
fate restricted during migration (Erickson
and Goins, 1995
; Wakamatsu et
al., 1998
).
There is evidence that a small proportion of NC cells, which migrate into
the epidermis, have both melanogenic and neurogenic potential in vitro
(Richardson and Sieber-Blum,
1993). This raises the possibility that for these cells,
melanocyte cell fate decision could be made after migration into the
epidermis. However, there is no evidence that this occurs in vivo. On the
contrary, studies in vivo indicate that the small number of NC cells with
neurogenic potential, and which migrate into the epidermis, are eliminated by
apoptosis (Wakamatsu et al.,
1998
).
It is unknown whether the cells in the dorsal NT are irreversibly fate
determined once they begin to express Kit and before they have emigrated. At
this stage, Kit is the only known melanocyte marker expressed on these cells.
The expression of a transcription factor, MITF, which is crucial for
melanocyte development (Hornyak et al.,
2001; Opdecamp et al.,
1997
), is also useful for identification of putative melanocyte
progenitors. MITF is probably expressed soon after Kit, and rare MITF cells
have been found close to the dorsal midline of the NT, just underneath the
surface ectoderm (Nakayama et al.,
1998
). The precise relationship between Kit and MITF is unclear,
but whereas initial expression of both of these proteins is independent of the
other, subsequently MITF is required for the maintenance of Kit, and Kit
modulates MITF (Hou et al.,
2000
; Opdecamp et al.,
1997
). Trp2 is only expressed later, possibly at the point the
cells encounter the ectoderm (Hornyak et
al., 2001
). It would thus not be surprising if this first step,
expression of Kit, in melanocyte development were reversible. This would be in
accord with our previous proposal that cell fate decision is a continuous
process, beginning as soon as the NC forms, but which may be reversible at the
early stages (Murphy and Bartlett,
1993
). However, early functional consequences of melanocyte
specification are evidenced by grafting experiments in aves
(Erickson and Goins, 1995
),
which showed that only NC cells, specified to the melanocyte lineage, migrate
along the dorsolateral path from the NT.
Origin of melanocytes in the head
In the head, Kit+ cells develop on the dorsal midline only at
the midbrain-hindbrain junction. The cells from this region migrate to the
ectoderm in the head, as well as forming a stream of cells in the mesenchyme.
We have not characterized which structures in the head are populated by this
stream, but initial observations indicate that it could provide melanocytes
for the ear and eye. The focal source of melanocytes in the head has not been
defined before, but other studies are consistent with our findings. Kit
antibody staining on the surface of the embryo revealed two populations of
Kit+ cells in the head region: (1) over the midbrain area, which
corresponds to the cells we describe originating from the midbrain-hindbrain
junction; and (2) a more caudal group, corresponding to the cells we see that
have migrated from the cervical area of the trunk NT
(Yoshida et al., 1996).
Furthermore, the expression of MITF on the surface of the head is essentially
the same as we see with Kit (Nakayama et
al., 1998
). Finally, in other studies that traced melanoblast
clones in dopachrome tautomerase-lacZ transgenic mice embryos, the clones
showed a restricted distribution on the surface of the head at early
developmental times, similar to what we observe
(Wilkie et al., 2002
).
Other structures in the head express Kit, but they are not derived from the
Kit+ cells in the dorsal NT. If any of these Kit+ cells
are NC derived, they must be derived from cells that did not express Kit at
the time of migration. We showed this in the branchial arches and cranial
ganglia, which express Kit well before there is any Kit expression in the
dorsal NT. These findings are supported by tracing studies in mice, which show
that NC migration into the branchial arches is over by early E8, and that
migration into the cranial ganglia is over slightly later
(Osumi-Yamashita et al., 1994;
Serbedzija et al., 1992
). This
is at least 36 hours before we see any migration of Kit+ cells in
the head. Some of the very early migrating NC cells may be derived from
epidermal ectoderm (Nichols,
1981
), and in our studies there is a suggestion of this from the
very close association of the developing trigeminal ganglion with the ectoderm
(Fig. 7D).
In studies of melanocyte development in the head in aves, early migrating
branchial arch-derived NC cells do not differentiate into melanocytes in
vitro; melanoblasts only appear late in NC development and do not invade the
branchial arches (Reedy et al.,
1998b). These findings are consistent with ours, that melanocytes
are derived from a discrete population of NC cells in the head.
NC lineage segregation in the NT
Our results provide evidence that different populations of NC precursor
cells arise within distinct spatially and temporally defined regions of the NT
(see Fig. 8 for a summary). (1)
The Kit+ melanocyte progenitors, located most dorsomedially in the
premigratory crest. Along the embryonic axis, they are found predominantly at
the midbrain-hindbrain junction and the cervical trunk, with significant
numbers also in the lower trunk. This axial pattern corresponds with the
variable densities of melanoblasts found lateral to the NT in the mouse embryo
(Baxter et al., 2004). The
Kit+ cells begin to express p75 from E10.5, when they start to
migrate, suggesting a link between p75 expression and migration for these
cells. (2) The p75+/Kit cells, which migrate
ventrally. These cells arise from E9.5 in the premigratory crest and are
ventrolateral to the Kit+ cells in the areas where these two cell
types are found. They are unlikely to generate melanocytes because of their
ventral migration and their lack of Kit expression. We have never found
Trp2+ melanocyte progenitors in the ventral migration path (data
not shown). Furthermore, neural crest cells isolated from the ventral path do
not give rise to melanocytes when explanted in culture
(Reedy et al., 1998a
). Thus,
this p75+/Kit population most likely gives rise
only to ventral NC derivatives, such as peripheral neurons and glia. These
cells may correspond to a population of NC cells that migrates ventromedially
from E9.5 through E10.5 (Serbedzija et
al., 1990
). One way to verify this would be to label the dorsal NT
with a traceable dye in a mediolateral pattern at E9.5-E10, to see if and
where the p75+ cells migrate.
A third population of premigratory cells must also exist in the dorsal NT
that expresses neither Kit nor p75: these cells must give rise to the earliest
migrating NC cells that we detect with p75 staining along the ventral
migration path at E9. This early population may be the same as an early NC
population that migrates ventrolaterally up until E9.5
(Serbedzija et al., 1990).
Our findings can be compared with the zebrafish NC, where there is good
evidence for cell lineage specification within the premigratory NC
(Raible and Eisen, 1994;
Schilling and Kimmel, 1994
).
In the head of the zebrafish, there is also evidence for lineage segregation
based on mediolateral location within the NC, with neurogenic cells most
lateral, mesenchymal cells most medial, and melanocytes between
(Schilling and Kimmel, 1994
).
Cranial NC cells in zebrafish are laterally segregated from the neural keel as
a coherent mass, in a very different arrangement to that in tetrapods. Because
of this pronounced difference in structure, it is difficult to know how
similar the cranial NC in zebrafish is to the premigratory NC in tetrapods
(Schilling and Kimmel, 1994
).
Our findings showing a related mediolateral segregation of cell lineage in the
mouse trunk suggest that this kind of NC segregation applies to vertebrates in
general. However, our findings are not equivalent to zebrafish. In the mouse
head, melanocyte progenitors are restricted to the midbrain-hindbrain junction
and we have not found evidence for a mediolateral arrangement of NC cell types
in this region.
Our observations on the timing of migration are also consistent with
previous findings that the timing of migration influences the range of neural
crest derivatives (Raible and Eisen,
1994; Serbedzija et al.,
1994
), and that only late migrating NC cells are melanogenic
(Erickson and Goins, 1995
;
Reedy et al., 1998a
;
Wehrle-Haller et al., 2001
;
Wehrle-Haller and Weston,
1995
; Yoshida et al.,
1996
).
A number of studies have traced the fate of individual dorsal NT precursor
cells in vivo in tetrapods, and provide strong evidence that these cells are
multipotential precursors for both NT cells and different NC lineages
(Bronner-Fraser and Fraser,
1989; Bronner-Fraser and
Fraser, 1988
; Collazo et al.,
1993
; Frank and Sanes,
1991
; Serbedzija et al.,
1994
). As a large number of clones gave rise to both NT and NC
cells, it follows that a large proportion of the traced cells divided and
generated two or more cells within the dorsal NT. Within the NT, the
individual cells of a developing clone could thus be separately induced to
either become a ventrally migrating NC cell, to express Kit and migrate
dorsolaterally, or to become an NT cell. This would be consistent both with
the multipotentiality of these cells, as well as with melanocyte fate decision
within the NT.
How is the melanocyte lineage induced?
If our interpretations are correct, then NT cells right on the dorsal
midline must be specifically induced to express Kit and melanocyte fate.
Factors that are at their highest concentration on the midline may be involved
in the induction process. In zebrafish, the medial expression of Wnts is
implicated in melanocyte specification in the head
(Dorsky et al., 1998). If Wnt
signalling is ablated specifically in NC cells in mice, melanocytes and
sensory neurons are lost, but not autonomic neurons
(Hari et al., 2002
). In avian
NC cultures, Wnt3a stimulates melanocyte production but neuron differentiation
is inhibited (Jin et al.,
2001
). Furthermore, the Wnt modulator, cfrzb1, is
expressed in neuronal and glial precursors and not in melanoblasts
(Jin et al., 2001
). Therefore,
it is possible that Wnt signalling results in neural/neuronal specification
when Frzb1 is expressed, and in melanocyte specification in its
absence. Precisely where Frzb1 is expressed in the NT needs to be
determined. Other signalling pathways may also be involved.
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ACKNOWLEDGMENTS |
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