THE INTERNATIONAL JOURNAL OF

Int. J. Dev. Biol. 53: 851-856 (2009)

DEVELOPMENTAL

BIOLOGY

doi: 10.1387/ijdb.072502sk

www.intjdevbiol.com

How animals get their skin patterns:
fish pigment pattern as a live Turing wave
SHIGERU KONDO*,1, MOTOKO IWASHITA2 and MOTOOMI YAMAGUCHI3
1Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan, 2Unit on Neural Circuits

and Adaptive Behaviors, Genes, Cognition and Psychosis Program, National Institute of Mental Health /NIH, Bethesda, MD, USA and 3Center of Developmental Biology, Riken, Chuo-ku, Japan

ABSTRACT It is more than fifty years since Alan Turing first presented the reaction-diffusion (RD)model, to account for the mechanism of biological pattern formation. In the paper entitled "Thechemical basis of morphogenesis", Turing concluded that spatial patterns autonomously made in
the embryo are generated as the stationary wave of the chemical (cellular) reactions. Although
this novel idea was paid little attention by experimental biologists, recent experimental data aresuggesting that the RD mechanism really functions in some of the course of animal development.
Among the phenomena in which involvement of the RD mechanism is suspected, the striped
pigment pattern of zebrafish has been highlighted as an ideal model system for the following
reasons: the stationary wave made by the RD mechanism stays alive and can be observed only inthe fish skin; and in zebrafish, we can utilize genomic information and molecular genetic
techniques to clarify the molecular basis of pattern formation. In this review, we summarize recent
progresses in the study of zebrafish pigment pattern formation that is uncovering how the RD
wave is made and maintained in the skin.

KEY WORDS: pattern formation, reaction-diffusion system, zebrafish, pigment cell, Turing

Mechanisms of biological pattern formation
One of the major issues in developmental biology is how
positional information is laid down in the tissues and bodies ofanimals. Research in molecular genetics during the past three
decades has proved that eggs already possess a substantial
degree of positional information as evidenced by the localized
distribution of key molecules proteins or ribonucleic acids (RNAs).
(Gilbert, 2003; Wolpert, 2006) Cells in an embryo are able to readtheir position from the concentration of such molecules, and are
thereby induced to undergo position-specific differentiation. The
differentiated cell can produce signaling molecules that are usedas secondary positional information. By repeating this induction
cascade, it is theoretically possible to determine positional information in later stages.(Wolpert, 1969; Wolpert, 1989) This simple
mechanism, generally called “pre-pattern theory” or “morphogen
theory,” has been experimentally proved in many morphogenetic
events in early development, and is widely accepted as a mecha-

nistic principle that functions when spatial patterns are laid downin the embryos. However, this simple mechanism is apparently
not fully capable of accounting for the complex structures of theadult body because its complexity far exceeds the positional
information of the egg.
Moreover, many examples have shown that animal development is quite robust against the artificial disturbance of primarystructures. For example, hydra can regenerate correct structuresfrom an aggregate of dispersed cells.(Bode, 2003; Guder et al.,2006; Wolpert et al., 1971) When a planarian is cut into pieces, thecomplete structure is regenerated from each piece(Agata et al.,2007; Best and Morita, 1982), suggesting that there is no fixed
origin of a “morphogen.” This amazing robustness of animal
development implies the existence of the second principle ofspatial pattern formation, which is independent of the pre-existing

Abbreviations used in this paper: RD, reaction-diffusion; RNA, ribonucleic acid.

*Address correspondence to: Dr. Shigeru Kondo. Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
Fax: :+81-6-6879-7977. e-mail: shigerukondo@gmail.com or skondo@fbs.osaka-u.ac.jp

Published online: 18 June 2009.

ISSN: Online 1696-3547, Print 0214-6282© 2009 UBC Press
Printed in Spain

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positional information that is established in the egg.

A

RD mechanism: an autonomous mechanism that cangenerate the spatial pattern
There are several theoretical mechanisms that are able togenerate spatial patterns autonomously without any pre-pattern(Meinhardt, 1982; Murray and Oster, 1984). Among them, one of
the most plausible in biological systems is the reaction-diffusion(RD) mechanism which was first presented by A. Turing in 1952
(Gierer and Meinhardt, 1972; Turing, 1952), and mathematicallyrefined by mathematical biologists (Meinhardt and Gierer, 2000a;
Murray, 2003). In the model, the spatial pattern is made as
stationary waves generated by the interactive RD of putative
chemical substances. According to mathematical modelling using
computer simulation, an RD system is able to generate stable andevenly-spaced patterns when the whole network satisfies a condition of “local activation and long range inhibition.”(Meinhardt
and Gierer, 2000a) The spatial patterns made by the system(e.g.,”RD pattern” or “Turing pattern”) do not need any prepattern, and autonomously regenerate when artificially disturbed.
In the 1970s, extensive computational studies showed that the
RD model can reproduce a variety of morphogenetic phenomenaof animal development, those that the pre-pattern model cannot
explain. (Meinhardt, 2003; Murray, 2003)
However, in spite of its theoretical importance, until very
recently, Turing's theory was not widely accepted by experimental biologists for two major reasons. First, the main concept of thetheory, namely that the pattern is made by a wave, is quite
unfamiliar to many experimental biologists. Second, it is difficult
to prove the existence of such a wave by some experiment. In
order to prove that the RD mechanism functions in a particularmorphogenetic event, we need to show that the pattern possesses the dynamic nature of the RD wave.

Morphological phenomena in which the involvement of
the RD mechanism is suspected
For about 40 years after Turing’s original work, studies of RD
mechanisms were almost exclusively theoretical, and there waslittle convincing experimental evidence for Turing patterns in any
system, biological or otherwise. The first clear experimental
support for this mechanism came in chemical experiments in theearly 1990s. Castets et.al. and Ouyang et. al. succeeded in
making the Turing pattern using complex chemical reactions.
(Castets et al., 1990; Ouyang and Swinney, 1991) These works
encouraged biologists to study the theoretical mechansim, andKondo and Asai found that the pigmentation pattern on the skin ofan angel fish moved exactly in the manner that Turing’s theory
predicted (Kondo and Asai, 1995).
They recorded the pattern change of the pigment pattern of amarine angelfish, Pomacanthus imperator, and suggested thatthe time course of the pattern change is identical to that predicted
by Turing’s theory. The involvement of the Turing mechanism is
now seriously investigated experimentally in several morphological events; hair pattern of mammals (Jung et al., 1998; Nagorcka,
1983; Sick et al., 2006), feather patterns of birds (Harris et al.,2005; Jiang et al., 2004; Prum and Williamson, 2002), regeneration of hydra (Bode, 2003; Gierer et al., 1972; Technau et al.,

B

C

D

E

Fig. 1. Dynamic pattern change in the fish and simulation. (A) Changeof stripe pattern in the skin of Pomacanthus imperator during 90 days and(B) the prediction made by simulation of a reaction diffusion mechanism.
Sliding of the branch point is observed in both systems. Change of spot
pattern occurring in the skin of a catfish, Plecostoms sp., during 14 days
(C,D) and the simulation (E). Division (C) and insertion (D) of the spot are
observed in both real fish and in the simulation based on the RD model.
From (Kondo and Asai, 1995) and (Asai et al., 1999).

2000) and right-left determination in the vertebrates (Hamada etal., 2001; Hamada et al., 2002; Nakamura et al., 2006). In thesecases, candidates for the core functional molecules of patternformation were proposed.
For example, in the case of the mouse hair pattern, Sick et. al.
suggested that the WNT and DKK proteins play the role of theputative activator and inhibitor in the reaction-diffusion system(Sick et al., 2006). Moreover, by artificially changing the parameters of the interactions, it is possible to induce the pattern changethat is predicted from the simulation, suggesting that an RD
mechanism underlies the determination of the hair distribution(Sick et al., 2006). However, most of these morphogenetic events
are irreversible, and the patterns that we can observe are completed and fixed ones. Therefore, it is usually impossible todirectly detect the existence of the ”wave” in the course of theTuring patterns in fish skinpattern-forming event.

Characteristic movement of the RD wave is visible in
the animal skin
To date, pigmentation patterns in animal skins (Murray et al.,
1990; Murray and Oster, 1984), feathers of birds (Harris et al.,2005; Prum and Williamson, 2002), and shells of the snails(Meinhardt, 2003) are the only examples in which we can detectthe dynamic nature of Turing waves as a time course of the patternchange. Especially, the 2D skin pattern of the fish is quite
convenient to study because waves are sometimes active evenwhen the fish has reached adulthood.
For example, when a striped angel fish ( Pomacanthus
imperator) grows, the branching points of the stripes slide horizontally as the zip opens, and add a number of stripes; eventually
the spacing between the stripes remains stable (Fig. 1A) (Kondo
and Asai, 1995). In the case of spotted catfish (Plecostoms sp.),
both division of the spots and insertion of the new spots occur toretain the density and size of the spots (Fig. 1B) (Asai et al., 1999).
Both stripes and the spots are the most typical 2D patterns
generated by the RD mechanism, and the time course of thepattern change possesses the characteristics of the dynamics of
RD waves, strongly suggesting that the RD mechanism underlies
the process of pigment-pattern formation of fish.

Zebrafish as a model system for studying patterning
mechanisms
In order to understand the principles of autonomous patternformation controlled by the dynamic mechanism, it is important to
identify the molecular-level network that functions in skin patternformation of fish where the wave is active. Observation on the
dynamics of the molecules related to the RD pattern formation
would dramatically contribute to our understanding of how animals keep the stable structure under an environment that is full of
disturbances. Fortunately, zebrafish, a small fish species withvery clear stripes in their trunk and fins, was selected as a model
animalÄfor biological studies, and for the use of the genomic
information and molecular-genetic technologies that are available to identify the molecular mechanism of pigment-patternformation.

The pigment pattern of zebrafish retains the dynamic
nature of the RD wave during the post embryonic stage
The pattern of skin pigmentation in zebrafish is composed ofthree types of pigment cells distributed in the hypodermis: melanophores, the main component of dark stripes; xanthophores,
the main component of light stripes; and iridophores (Hirata et al.,
2003; Kelsh, 2004). Although different from the stripes ofPomacanthus imperator, the stripes of zebrafish do not become
rearranged during normal growth, artificial disturbance of thepattern can induce the characteristic pattern change that is
specific to the RD mechanism. Kirschbaum (Kirschbaum, 1975a)
cut a piece of skin from the trunk and re-planted it at an angle toits original orientation. The stripes on the graft were terminated at
the edge of the transplant when the operation was completed.
But, he observed that the ends of the stripes moved and rejoined853

the end of the stripes of the host skin. Parichy and Turner (Parichy
and Turner, 2003) used a temperature sensitive mutant ofpanther(c-fms) gene, that is required to maintain both xanthophores
and melanophores, to erase the pattern and observe the regeneration of the pigment pattern. They found that when the pigment
cells were in the tail fins were‘killed, development of pigment cells
occurred to fill the vacant space, but the regenerated stripes often
lost the original directionality. These experiments suggest that the
stripes of the zebrafish stripes have the ability to repair themselves. and that the process is independent of the pre-pattern.
By using laser light to kill the pigment cells, it is possible toinduce more dynamic movement of the stripes that is characteristic of the stationary wave of the RD mechanism. Yamaguchi etal. (Yamaguchi et al., 2007) continuously killed the melanophores
in the dorsal two black stripes of the young (40 to 80 day) andobserved that the ventral black stripe bent and moved dorsally tofill the vacant space. (Fig. 2) This movement of the stripes strongly
suggests that the pigment pattern of the zebrafish is made andmaintained dynamically by the RD, or by a very similar mechanism.

A

B

3 days14 days

21 days

40 daysFig. 2.Dynamic change of the zebrafish pigment pattern induced bylaser experiment. (A) Time course of the pattern change. Melanophores
in upper two black stripes are killed by laser light. (B) Time-lapse captured
images of the regeneration process produced by simulation of reactiondiffusion mechanisms. From Yamaguchi et al. (2007).

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S. Kondo et al.

A

E

B

F

C

G

D

H

Fig. 3. Pigment patterns in zebrafish mutants. (A) Wildtype; (B)sparse; (C) nacre; (D) puma; (E) panther; (F) jaguar (obelix) and (G)leopard.

Another important suggestion which arises from these experiments is that the pigment cells do not simply make the hidden
pattern visible, but are the major players in the pattern formation.
Therefore, to uncover the mechanism, the most critical stepshould be the identification of the interactions between the two
types of pigment cells (melanophores and xanthophores).

Mutants that affect both development of pigment cells
and the resulting pattern
Several mutants that affect the skin pigment pattern have been
isolated from large-scale screening ethylnitrosourea (enu) chemical mutagenesis and the selection of spontaneous mutations(Haffter et al., 1996; Kelsh et al., 1996; Odenthal et al., 1996).
Illustrations and summaries of the experimental data from thesemutants are shown in Table 1 and Fig. 3. By gene cloning andfunctional analysis using a series of elegant chimera experiments, their functions in the pigment cell development is gradually
becoming clear.
These mutants are classified into two categories: those with adefect in the development of pigment cells; and those with normal
development of pigment cells at the embryonic stage, but with adisrupted pattern in the adult fish. Molecular genetic studies of themutants in the first category have shown that nacre (Lister et al.,1999), sparse (Parichy et al., 1999), and rose (Parichy et al.,2000a) are required for the development of melanophores, andthat panther (Parichy et al., 2000b) is required for the develop-

ment of xanthophores. The nacre gene codes a transcription
factor Mitf1 that is required by the cells to develop into melanophore precursor. Sparse and panther code the class II receptor
tyrosine kinases, c-kit and c-fms, respectively. rose codes theendothelin receptor b1. sparse fish lack embryonic melanophores, but the adult melanophores are normally integrated in the
stripes. The number of embryonic melanophores in rose fish isnormal, but a reduced number of adult melanophores compose
the disturbed stripe (Johnson et al., 1995b). The double mutant ofthese genes loses almost all the melanophores, suggesting that
there are two different populations in the melanophores, and only
the adult type is required for the stripe pattern formation (Johnson
et al., 1995b).
Interestingly, when one of the pigment cell type failed todevelop, other type of pigment cells fail to localize to their normal
positions (Johnson et al., 1995a; Lister et al., 1999; Parichy et al.,2000a; Parichy et al., 2000b; Parichy et al., 1999; Rawls et al.,2001). nacre fish lack all melanophores and panther fish lack
xanthophores. In both cases, the remaining pigment cells cannot
form clear stripes but disperse randomly or form aggregates of
uncertain shape. However, when a pigment cell type that is lost in
the mutant is introduced, clear stripes are regenerated only in theregion where both types of pigment cells exist. These experimental results show that mutual interaction between melanophores
and xanthophores plays a critical role in the generation of skinpigmentation pattern (Kelsh, 2004; Maderspacher and NussleinVolhard, 2003; Parichy and Turner, 2003; Parichy et al., 2003).

Mutants that affect the pigment pattern, but not thedevelopment of pigment cells
Mutants of jaguar/obelix(Maderspacher and Nusslein-Volhard,2003) and leopard (Kirschbaum, 1975b; Maderspacher andNusslein-Volhard, 2003) belong to this second category. In thesemutants, development and distribution of the pigment cells isnormal in embryos and young fish (~4weeks). In adult fish,
although development of pigment cells is normal, their spatial
arrangement (pattern) is changed, suggesting that these genes
are specifically required for pattern formation. The jaguar mutant
fish have wider stripes and the leopard fish have spotted patterns.
Maderspacher et al. performed a series of chimera experimentswith the mutants, and deduced the role of each gene in the pattern
forming mechanism as follows. Jaguar/obelx is required in melanophores to promote their aggregation and to control boundary
integuity. The leopard gene regulates homotypic interaction withinboth melanophores and xanthophores. Further, both are required

TABLE 1
SELECTED GENES INVOLVED IN PIGMENT PATTERN FORMATION IN FISH
MutantGene

Pattern

Melanophore

Xanthophoresparsekit /receptor tyrosine kinase

Stripe, boundary is slightly ambiguous

EM absent Present

Present

iridophore
Present

rose

ednrb1/G-protein coupled receptor

Fewer stripes, but normal in fins

LM absent

Present

Absentpuma

not cloned

Purely formed

LM absent

Present

Present

nacre

mitf1/transcription factor

Clusters of xanthophores, but purely striped

AbsentPresent

Present

pantherfms /receptor tyrosine kinase

Scatterd melanophores

Fewer

AbsentPresent

jaguar(obelix)

kir7.1/potassium chnnel

Wider stripes

Present

Present

Present

leopardconnexin41.8/ gap junction

Spots

Present

Present

Present

Modified from (Kelsh, 2004)

Turing patterns in fish skin
to control the boundary shape (Maderspacher and NussleinVolhard, 2003). The positional cloning of the jaguar mutant
revealed that this gene codes a inwardly rectifying potassiumchannel, Kir7.1 (Iwashita et al., 2006). Kir channels are a group of
ion channels which transfer potassium ions unidirectionally fromoutside to inside the cell (Doring et al., 1998; Kim et al., 2000;
Kusaka et al., 2001; Nakamura et al., 2000; Shimura et al., 2001).
It is known from the study of cultured cells that this class ofchannels is responsible for the stability of membrane potential
and sensitivity to the external signals (Suzuki et al., 2003;
Wischmeyer et al., 2000; Yasuda et al., 2003). Recently Jantzi et
al. reported that the kir channel (Kir2.2) facilitates cell-to-cellcommunication that propagates the contraction signal in hamster
retractor muscle feed artery (Jantzi et al., 2006). In zebrafish, theKir7.1 gene is expressed in melanophores (Iwashita et al., 2006),
suggesting that the channel controls the interaction of the melanophores. The gene responsible for the leopard mutant is cloned
and identified to be a component of gap junctions, connexin41.8(Watanabe et al., 2006). Connexin41.8 is expressed in manykinds of skin cells including melanophores and xanthophores. As
the expression level of the connexin41.8 gene is very low in cellsof the zebrafish skin, little is known about the function and role ofthe molecule in pigment-pattern formation. However, Johnson etal. reported recently that another class of gap junction gene,connexin43, encodes the shortfin (sof) gene, which controls thelength of the fins of the zebrafish (Iovine et al., 2005). This fact isquite interesting because it implies that a similar mechanism
could control the size of limbs and the 2D patterns in the skin.

Future directions
Although molecular genetic studies have identified genes andmolecules involved in pigment-pattern formation in fish, the questions as to how they are organized and how they generate the RD
wave, remain largely unknown. To understand pigment-patternformation, it is necessary to integrate all the molecular reactions
and deduce how such complex systems behave. For this purpose, the framework of RD mechanism is useful. In most of themathematical models of the RD systems, the putative molecular
network is composed of chemicals that control the synthesis ofmolecules and their diffusion in the field. However, it is also
possible to compose an equivalent network with the interaction of
two types of cell (melanophores and xanthophores). Therefore
there is no theoretical difficulty in applying the model to zebrafish
pigment-pattern formation.
Mathematical studies on RD and related autonomous patternforming systems, revealed that the necessary conditions for theformation of a spatial pattern (spots and stripes) is the combination of “local activation” and “long range inhibition” (Meinhardt and
Gierer, 2000b). Recentry, Nakamasu estimated the in vivo interactions between the pigment cells by observing regeneration in
the area where the pigment cells in the surrounded region were
killed by laser (Nakamasu et al., 2009). They found that the effectof xanthophores on the melanophore is different depending on the
distance of the cells, and the deduced cell-cell interaction network
is consistent with the “local activation and long range inhibition”
rule. Temporally, we have little experimental data which connects
molecular data to the macroscopic observations which suggest
the involvement of the Turing mechanism in pigment pattern855

formation. Use of advanced live-imaging techniques will help toassess whether or not the functioning molecules behave as themodel predicts, and will also help to identify the molecular-levelnetwork. With the cooperation of advanced molecular genetics
and mathematical modeling, the long unsettled question of how
animal skin patterns are generated will be solved in the near
future.

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Turing patterns in fish skin

Further Related Reading, published previously in the Int. J. Dev. Biol.
See our Special Issue Developmental Morphodynamics edited by Lev Beloussov and Richard Gordon at:
http://www.ijdb.ehu.es/web/contents.php?vol=50&issue=2-3
See our Special Issue Fertilization, in honor of David L. Garbers and edited by Paul M. Wassarman and Victor D. Vacquier at:
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