Max-Planck-Institut für Entwicklungsbiologie, Abt. III/Genetik, Spemannstrasse 35, 72076 Tübingen, Germany
* Author for correspondence (e-mail: florian.maderspacher{at}tuebingen.mpg.de)
Accepted 1 April 2003
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SUMMARY |
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Key words: Melanophore, Xanthophore, Zebrafish, Pigment pattern
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INTRODUCTION |
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The pigment patterns of many fish and amphibians are comprised of
alternating arrays of different neural crest-derived pigment cell types.
Often, these cells are already differentiated as the pattern forms, making a
mechanism as described above unlikely. Characterisation of these patterns
mainly carried out in amphibian larvae has implicated a variety of cell
behaviours such as migration, cell-substrate and cell-cell interactions in the
generation of pigment patterns (e.g.
Epperlein and Claviez, 1982;
Epperlein and Löfberg,
1990
; Macmillan,
1976
; Parichy,
1996a
; Parichy,
1996c
; Tucker and Erickson,
1986
; Twitty,
1945
). However, the identification of specific factors involved in
pigment pattern formation is difficult in non-genetic model systems.
The emergence of zebrafish as a model system has resulted in a collection
of mutants affecting various aspects of pigment cell development and
physiology. One major class of these mutants, such as colourless
(Dutton et al., 2001),
nacre (Lister et al.,
1999
), sparse
(Parichy et al., 1999
),
rose (Parichy et al.,
2000a
) and fms
(Parichy et al., 2000b
), shows
a pigment cell phenotype already during early larval stages. Molecular
analysis of some of these mutants has revealed a high degree of functional
conservation with genes previously implicated in melanocyte development in
mice (Lister, 2002
). Another
class of mutants, such as asterix, obelix
(Haffter et al., 1996b
),
leopard (Kirschbaum,
1975
), puma (Parichy
and Turner, 2003b
; Parichy et
al., 2003
) and hagoromo
(Kawakami et al., 2000
), shows
a late phenotype during formation of the adult pigment pattern. So far, only
one of these genes, hagoromo (hag), has been cloned.
hag encodes a dactylin homologue
(Kawakami et al., 2000
) and
perturbs the pattern locally upon mutation.
In zebrafish, the adult pigment pattern
(Goodrich and Nichols, 1931)
(reviewed by Quigley and Parichy,
2002
) consists of alternating stripes formed by melanin-bearing
melanophores and pteridine containing xanthophores
(Bagnara, 1998
). The third
major class of chromatophores in zebrafish, silvery iridiophores, is likely to
be irrelevant for stripe formation, as tissues devoid of iridiophores also
display a striped pattern. At the onset of adult development, this pattern
evolves through the alignment of newly differentiating pigment cells with a
lateral melanophore stripe that persists during larval stages
(McClure, 1999
;
Milos et al., 1983
). One major
question is therefore how the cells become organised into these domains. In
principle, this might be accomplished by filling in a prepattern that is set
up independent of the pigment cells. Alternatively, mutual interactions
between the pigment cells might define the striped domains. Other crucial
characteristics of this pattern are the strict separation between regions
occupied by either cell type and the straight boundary between them. How these
features are generated and which cell behaviour underlies their formation
remains largely obscure. In this study we show, using mutants that abolish
formation of either melanophores or xanthophores, that presence and
juxtaposition of both pigment cell types is necessary and sufficient for
stripe formation. Thus, the domains appear to be largely defined by
short-range interactions among pigment cells. Based on the analysis of
patterns formed in the presence of only one cell type, we classify the cell
behaviours during stripe formation into homo- and heterotypic interactions. In
light of this distinction we analyse the phenotypes of two mutants,
leopard (leo) and obelix (obe), that
specifically alter the adult pigment pattern in a qualitative way and assay
their cell type specific requirements by mosaic analyses. leo and
obe affect different subsets of these cell behaviours and constitute
central components of the stripe-forming system.
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MATERIALS AND METHODS |
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Cell-transplantation
For all transplantations, donor embryos were homozygous for the
ß-Actin GFP transgene (bpeGFP) in combination with various mutant
genotypes. For leo and obe, the two strongest alleles,
tq270 and td15, were used. Cell transplantations were
performed essentially as described previously
(Kane and Kishimoto, 2002).
Surviving larvae were sorted on day 2 according to presence of pigment cell
clones and raised to adulthood for analysis.
Image acquisition and analysis
For images of the developmental series, juvenile fish of defined genotype,
age and size were maintained individually. Fish were anaesthetised in 0.04%
Mesab and mounted on a glass slide in 3% methylcellulose. At 1 day intervals,
body size was measured and pictures of the same region of the flank posterior
to the dorsal fin were captured using a Zeiss AxioCam mounted on a dissecting
microscope. Images of xanthophore autofluorescence and GFP fluorescence were
taken with the same setup, using UV epiluminescence and a GFP filter. For
images of the adults, male fish were sacrificed and fixed overnight in
ice-cold 4% PFA. Scales and pectoral fins were removed and fish were mounted
in 0.5% Agarose. All images were processed using Adobe Photoshop 6.0. Direct
comparisons of cell positions on at 24-hour intervals were made by overlaying
images manually to a maximum overlap of cell positions and marking cells that
had changed position.
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RESULTS |
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To study the pattern formed by xanthophores in the absence of melanophores,
we used mutants for nacre (nac; mitfa
Zebrafish Information Network) (Lister et
al., 1999), a zebrafish homologue of the mammalian microphthalmia
gene (Hemesath et al., 1994
;
Hodgkinson et al., 1993
).
nac mutants are homozygous viable and completely lack melanophores in
larval as well as adult stages. During larva to adult transition, xanthophores
in nac mutants (Fig.
1J) first appear adjacent to the horizontal myoseptum in
essentially the same position as in wild type. However, their appearance is
strongly delayed, and a fraction (4/9) of the individuals analysed showed no
xanthophores by day 30. Xanthophores appear in small clusters of only a few
cells and seem to expand their domain much slower than in wild type. In
nac adults (Fig.
1C,F), xanthophores occupy a coherent longitudinal field of cells
straddling the horizontal myoseptum and irregular patches further ventrally.
Between these domains, large areas are completely devoid of xanthophores.
We next asked whether the altered positioning of pigment cells in nac and fms mutants is solely due to the absence of one cell type and thus reflects their intrinsic positioning behaviour. To this end, we generated genetic mosaics by transplanting wild-type blastula cells marked by constitutive GFP expression (bpeGFP) into homozygous nac and fms mutants. Embryos resulting from these experiments were raised to adulthood and patches (`clones') containing the pigment cell type normally absent from the respective mutant were analysed.
Upon transplantation of bpeGFP blastula cells into homozygous nac
mutants, all melanophores observed in transplanted fish are of donor origin,
as nac has been shown to be autonomously required in melanophores
(Lister et al., 1999), whereas
xanthophores are both donor as well as host derived. In all animals analysed
(n=26) the melanophores within such clones formed stripes that
alternate with xanthophore stripes, resulting in a locally rescued pattern
that is indistinguishable from wild type
(Fig. 2C). The xanthophore
stripes within such clones contain donor-derived, GFP-positive xanthophores as
well as host derived ones. This shows that nac mutant xanthophores
retain the ability to organise into stripes. Only xanthophores that are in
contact or close proximity to melanophores will contribute to the striped
pattern, whereas donor as well as host derived xanthophores further away from
the melanophore clone assume a distribution as seen in untransplanted
nac mutants (Fig. 2D).
This indicates that indeed the absence of melanophores causes the altered
xanthophore distribution in nac mutants. Moreover, the fact that
xanthophores will form stripes only in the vicinity of melanophores suggests a
short-range mode of interaction between melanophores and xanthophores during
stripe formation. The cells transplanted at blastula stages will give rise to
a variety of tissues in the adult. However, we found that striped patterns
always occur where xanthophores and melanophores are in proximity,
irrespective of the origin of the underlying tissue.
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Taken together, these findings show that juxtaposition of melanophores and xanthophores is necessary and sufficient for stripe formation.
obe and leo affect stripe
integrity and shape respectively
The experiments outlined above indicate that stripe formation requires
interactions between the two pigment cell types. To look for factors that
might govern these interactions we investigated two mutants, leopard
(leo) (Kirschbaum,
1975) and obelix (obe)
(Haffter et al., 1996b
), that
alter the adult pigment pattern. Four dominant alleles of obe were
isolated in a large-scale mutagenesis screen
(Haffter et al., 1996a
) (F.M.
and C.N.-V., unpublished). Heterozygous adults display only two to three
melanophore stripes that are wider than in wild type and frequently
interrupted by xanthophores (Fig.
3B,L). This is most likely a dosage-dependent effect of
obe, as it is also observed in heterozygotes for the c7 deletion that
covers the obe locus (data not shown). In obe homozygous
adults (Fig. 3A,E) melanophores
are found in two broad longitudinal domains flanking the horizontal myoseptum.
Strikingly, the melanophore domains always contain interspersed xanthophores,
indicating that obe mutants lack the strict separation between the
two cell types seen in wild type.
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We next examined the ontogeny of the pigment pattern in individual
leo and obe mutant fish over the course of 14 days during
larva to adult transition. At the onset of adult pigment pattern formation in
wild type (Fig. 1G,H),
melanophores are differentiating in broad regions of the flank dorsally and
ventrally of the horizontal myoseptum, which bears melanophores of the larval
lateral stripe. Subsequently, xanthophores appear around the horizontal
myoseptum. Concomitantly, the melanophores in the flank begin to converge
towards the horizontal myoseptum by migration
(Parichy et al., 2000b),
whereas melanophores within the xanthophore stripe are eliminated. Thus, a
xanthophore stripe flanked by two melanophore stripes has formed. As
melanophores are cleared from dorsal and ventral regions, new xanthophores
appear, continuing the alternation of the pattern.
In obe mutants, the larval pattern (not shown) and the initial appearance of melanophores at 21 days are similar to wild type (Fig. 4A). During appearance of the xanthophores, melanophores fail to cluster and remain scattered instead. Furthermore, melanophores do not converge towards the horizontal myoseptum and persist in more ventral areas as well as within the xanthophore stripe. The xanthophores in obe mutants (Fig. 4B) appear initially in the same position as in wild type, but later start to emerge between the scattered melanophores, giving rise to the mixing pattern.
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Taken together, these data indicate that both leo and obe have a similar effect on melanophore behaviour, whereas only leo also affects xanthophore behaviour.
obe function is required by melanophores
To assay the cell-type-specific requirements for leo and
obe, we juxtaposed wild-type melanophores with mutant xanthophores
and vice versa. This was accomplished by transplanting mutant or wild-type
cells into nac single or double mutants, because in nac
mosaics all melanophores will be donor derived. These mosaics could then be
scored for formation of a wild-type or mutant pattern. As only one of the cell
types will be mutant in a given mosaic condition, the type of pattern
generated in that condition indicates the cell types in which the formation of
the respective gene is required. Additionally, this experiment should also
allow to determine whether the genotype of the pigment cells themselves or
rather that of the underlying tissue is decisive for the type of pattern
formed. In order to confirm that obe or leo mutant patterns
could be reconstituted in mosaic experiments, we transplanted obe or
leo mutant cells into nac;obe or
nac;leo double mutant hosts, respectively, and found that in
both cases the mutant patterns were faithfully reproduced (data not shown).
Furthermore, all mosaic conditions for leo and obe generated
consistent patterns within the clones, irrespective of whether the underlying
tissue was wild type or mutant for obe, thus establishing a
requirement for both genes within the pigment cells.
We analysed the cell type specific requirements for obe by transplanting bpeGFP cells that are wild type for obe into nac;obe double mutants (Fig. 6A,B). To distinguish host and donor cells, the donor cells were marked by the gol mutation and GFP expression. In the mosaic adults analysed (n=24) melanophore clones always formed a wild-type-like stripe pattern with clear separation between melanophores and xanthophores (Fig. 6A). This was also the case when the vast majority of xanthophores within a clone was host derived and thus mutant for obe (Fig. 6B), showing that wild-type melanophores can form a regular boundary with obe mutant xanthophores. In the complementary experiment, obe mutant bpeGFP cells were transplanted into nac single mutant hosts, melanophore clones in all mosaics analysed (n=18) formed broad irregular domains, similar to the obe mutant pattern (Fig. 6D,E). In cases where most of the xanthophores were wild type, they mingled with obe- melanophores. Thus, both mosaic conditions indicate that the genotype of the melanophores determines whether a wild type or an obe mutant pattern is formed. Hence, obe function is required within the melanophores for spatial separation between the pigment cell types.
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With the complementary mosaic condition, transplantation of leo; bpeGFP cells into a nac single mutant host, a similar result was obtained (Fig. 6J,K). Again, none of the nac adults containing melanophore clones (n=18) showed a clear wild-type pattern in the clone. Instead, similar undulating stripes and spots were observed as for the inverse mosaic condition. In addition, leo mutant melanophores predominantly surrounded by wild-type xanthophores were forming spots, and hence a leo-like pattern. Thus, leo mutant melanophores can organise wild-type xanthophores into a leo-like spotted pattern. These findings indicate that leo, unlike obe, is required by both pigment cell types, and that compromising leo function in either melanophores or xanthophores alone is sufficient to generate a leo like pattern.
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DISCUSSION |
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In addition, the analysis of nac and fms mutants also
reveals which aspects of cell behaviour in particular depend on the presence
of the other cell types. The delayed appearance of xanthophores in
nac mutants could indicate an requirement of melanophores during
adult development for correct differentiation and/or proliferation of
xanthophores. Alternatively, this could be due to a direct requirement for
nac in xanthophore development, as in the embryo some xanthophore
precursors have been shown also to express mitf
(Parichy et al., 2000b).
Melanophores can aggregate independently of xanthophores, but they fail to
converge towards the horizontal myoseptum and also persist in areas from which
they are normally cleared (Parichy et al.,
2000b
). This indicates an attractive effect of xanthophores on
distant melanophores, which promotes their alignment on either side of the
xanthophore stripe. Conversely, within their domain, xanthophores might repel
melanophores.
The exact cellular mechanisms that underlie these interactions are still
unclear. It can be assumed that it involves an ability of the cells to
recognise each other and to aggregate. As pigment cells outside clones cannot
be organised into stripes at a distance, stripe formation appears to involve
mainly short-range interaction or even direct cell-cell contact. Indeed,
histological examination of adult dermis revealed intimate cell contact both
among and between cells of one type (F.M. and C.N.-V., unpublished). One
intriguing possibility is that differential affinities
(McNeill, 2000;
Steinberg, 1970
) between
pigment cells account for the spatially distinct domains of the pattern.
Clearly, cells in Drosophila wing imaginal disks display differential
affinities (Dahmann and Basler,
1999
; Dahmann and Basler,
2000
; Milan et al.,
2001
) during establishment of compartment boundaries. Given the
intimate contact and the aggregative behaviour of pigment cells in the adult,
one could envisage that affinities of melanophores and xanthophores for cells
of the same type could establish separation, whereas affinity for cells of the
other type might generate contact at the boundary.
Early features of the adult pattern can be formed in the absence of
one cell type
Apart from interacting with cells of the other cell type (heterotypic
interaction), pigment cells of one type also interact with each other
(homotypic interaction). This is evident from the fact that neither
xanthophores nor melanophores are randomly distributed in the absence of the
other cell type. Rather, cell-type-specific patterns are formed that can be
seen as the outcome of homotypic interactions reflecting the intrinsic
positioning behaviour of the cells. One key feature of these single cell type
patterns is the cells tendency to aggregate. The clustering of a fraction of
melanophores involves translocation of cells from an initially scattered
distribution towards the clusters formed during the early adult period
(Parichy et al., 2000b). Even
though xanthophores appear to change their position very little, if at all,
they also remain in coherent areas during expansion of the xanthophore domain.
Thus, both cell types must be able to establish and maintain cell-cell contact
either directly or indirectly.
Although formation of the hallmarks of the adult pigment pattern depends on
presence and interaction of melanophores and xanthophores, early features of
the wild-type pattern can be generated independently. The xanthophores in
nac mutants appear first close to the horizontal myoseptum, which
corresponds to the position of the first xanthophore stripe in wild type. In
addition, the initial position in which melanophores appear in fms
mutants is similar to wild type. This indicates that at least the initial
positioning of pigment cells during adult pattern formation is largely
independent of the presence of the other cell type. Instead, initial
positioning might be defined by anatomical landmarks, such as the horizontal
myoseptum. Notably, mutants in fss/Tbx24
(Nikaido et al., 2002;
van Eeden et al., 1996
)
disrupt horizontal myoseptum integrity, and display locally interrupted
stripes as adults (F.M. and C.N.-V., unpublished). The function of the
horizontal myoseptum as a starting point for stripe formation may be indirect,
as it also governs migration of the lateral line primordium, which has been
implicated in pigment pattern formation in salamanders
(Parichy, 1996a
;
Parichy, 1996c
).
obe controls boundary integrity by regulating
melanophore aggregation
Among the few mutants known to affect stripe formation in adult zebrafish,
leo and obe are probably central regulators of this process,
as they perturb stripe formation in all parts of the body. Furthermore, they
disrupt qualitative aspects of the pattern: the spatial separation of
melanophores and xanthophores (obe), and boundary shape
(leo). We believe that theses effects are not due to altered pigment
cell numbers, because mutants in genes known to affect the numbers of pigment
cells, such as sparse or heterozygosity for some semi-dominant
alleles of fms (Haffter et al.,
1996b; Odenthal et al.,
1996
) do not affect boundary integrity or shape in such a dramatic
way as leo or obe.
For obe, our analysis indicates that this gene is required in the melanophores to control their homotypic clustering. As xanthophores mingle with melanophores in obe mutants, melanophore clustering appears to be a major prerequisite for establishing spatial separation between melanophore and xanthophore stripes. The fact that in obe xanthophores also appear within the melanophore domains indicates an intrinsic affinity of xanthophores for the proximity of melanophores. This can overcome the tendency of xanthophores to remain clustered and to leave substantial regions of the flanks unoccupied, which occurs in the absence of melanophores. Maintaining melanophore clustering may not only be a way to establish separation, but might also regulate stripe width, as obe heterozygotes display wider melanophore stripes. The reduced melanophore clustering in this condition might result in a larger area occupied by more loosely clustered melanophores, whose clustering is just strong enough to prevent xanthophores from invading the melanophore domain.
At present, we can only speculate about which cell-biological aspect of
clustering behaviour might exactly be controlled by obe. It is
apparent from the ontogeny of wild-type pigment patterns
(McClure, 1999;
Parichy et al., 2000b
) that
melanophore clustering involves extensive translocation of melanophores and
thus requires an ability of these cells to migrate, to recognise each other
and to maintain contact. Notably, obe mutant melanophores neither
cluster nor converge individually towards the horizontal myoseptum, nor do
they disappear from within the xanthophore domain, suggesting that all of
these processes are dependent on obe. This defect might either be
caused by a reduced ability to recognise an attractive signal or by impaired
motility. One obvious candidate for an attractive signal guiding melanophore
aggregation is the kit ligand Steel
(Copeland et al., 1990
;
Huang et al., 1990
;
Zsebo et al., 1990
), which
stimulates melanocyte migration in the mouse
(Jordan and Jackson, 2000
;
Kunisada et al., 1998
).
Although a Steel homologue has not yet been identified in zebrafish,
sparse adults that are mutant for the Steel-receptor still display
melanophores aggregated in stripes
(Parichy et al., 1999
) (F.M.
and C.N.-V., unpublished), thus making a role for Steel-kit as essential
regulators of melanophore aggregation unlikely. Molecular analysis of the
obe gene will certainly shed light on its exact function.
leo affects multiple aspects of cell
behaviour
In contrast to the relatively restricted role of obe, leo affects
homotypic interactions of both melanophores and xanthophores, as revealed by
double mutant and mosaic analysis. The expansion of the xanthophore domain in
leo; nac double mutants is unlikely to be caused by
hyperproliferation of xanthophores, because in this condition the
differentiation of xanthophores is also strongly delayed (data not shown).
Instead, loss of leo function might weaken the cohesion between
xanthophores and allow for insertion of newly differentiating xanthophores,
thus expanding the domain. Interestingly, the disruptive effect of
leo on melanophore clustering is highly similar to obe.
Nevertheless, melanophores and xanthophores are still spatially separated in
adults, raising the question of why melanophores and xanthophores do not
mingle in leo in a similar fashion as in obe. This could be
explained by the concomitant alteration of homotypic xanthophore behaviour,
which might counteract the loss of melanophore clustering and re-establish
separation, albeit in a spotted pattern. However, when confronted with
leo mutant melanophores in mosaic experiments, xanthophores that are
wild type for leo do not mingle. Therefore, the effect of
leo on melanophore clustering must be quantitatively or qualitatively
different from that of obe.
Additionally, leo function is required in both melanophores and xanthophores for formation of a straight boundary, as loss of leo function in one cell type can impose a leo pattern on the other. This notion is corroborated by the fact that if only one cell type is mutant for leo, the pattern formed by mosaics displays a weaker leo phenotype (undulating stripes and spots) than the leo mutant. These findings strongly suggest that leo also affects heterotypic interactions between both cell types. In light of this idea, it is important to note that the straight interface between melanophore and xanthophore stripes can be interpreted as minimised contact and that reducing leo function gradually increases contact between melanophores and xanthophores by rounding the boundary between them. The leo gene is thus a central component of the stripe-forming system in that it controls both homotypic and heterotypic interactions of melanophores and xanthophores. This pleiotropy might be achieved by leo regulating several downstream components that control subsets of cell interactions. Alternatively, leo could favour homotypic interaction among melanophores and xanthophores at the expense of heterotypic ones between the two. Loss of leo function could then result in an increased tendency of either cell type to contact the other and hence to increase the boundary length between the two.
A model of cell interactions during stripe formation
Based on our findings, a model of interactions the adult pigment pattern in
zebrafish can be formulated (Fig.
7). The process is initiated by the differentiation of
melanophores at about 3 weeks of development
(Fig. 7A) and influenced by
size and age of the fish. Depending on the presence of melanophores,
xanthophores start differentiating in a relatively restricted domain
straddling the horizontal myoseptum (Fig.
7B). Positioning of this initial xanthophore stripe is presumably
directed by anatomical landmarks such as the horizontal myoseptum.
Concomitantly, melanophores start aggregating in an obe- and
leo-dependent fashion, and align with the xanthophore stripe.
Melanophore aggregation prevents further differentiation of xanthophores
within the melanophore domain, thus establishing spatial separation and also
regulates melanophore stripe width. Additionally
(Fig. 7C), xanthophores exert a
repulsive effect on melanophores present within their domain. The straight
interface between melanophores and xanthophores is subsequently formed by
leo-dependent regulation of both homo- and heterotypic cell
interactions (Fig. 7D).
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ACKNOWLEDGMENTS |
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