Summary. In mammals, the melanin pigment is
produced in two cell types of distinct developmental
origins. The melanocytes of the skin originate form the
neural crest whereas the retinal pigment epithelium
(RPE) of the eye originates from the optic cup. The
genetic programs governing these two cell types are thus
quite different but have evolved to allow the expression
of pigment cell-specific genes such as the three members
of the tyrosinase-related family. Tyrosinase, Tyrp1 and
Dct promoters contain a motif termed E-box which is
bound by the transcription factor Mitf. These E-boxes
are also found in the promoters of the corresponding fish
genes, thus highlighting the pivotal role of Mitf in
pigment cell-specific gene regulation. Mitf, which
displays cell type-specific isoforms, transactivates the
promoters of the tyrosinase gene family in both pigment
cell lineages. However, specific DNA motifs have been
found in these promoters, and they correspond to
binding sites for RPE-specific factors such as Otx2 or
for melanocyte-specific factors such as Sox10 or Pax3.
The regulation of pigment cell-specific expression is
also controlled by genetic elements located outside of
the promoter, such as the tyrosinase distal regulatory
element located at -15 kb which acts as a melanocyte-
specific enhancer but also protects from spreading of
condensed chromatin. Thus, by using the tyrosinase gene
family as a model, it is possible to define the
transcription factor networks that govern pigment
production in either melanocytes or RPE.
Key words: Melanocytes, RPE, Tyrosinase, Promoter,
The coat color phenotypes have been studied for
more than one century leading to the establishment of
some of the first rodent inbred strains (Morse, 1978).
The mouse strain DBA selected for the dilute, brown and
non-agouti coat color alleles was already established in
1909 by Little (Beck et al., 2000). An albino strain was
used to first demonstrate Mendelian inheritance of a
genetic trait in mammals in 1903 (Castle and Allen,
1903; Beermann et al., 2004). Thus, pigment genes were
“pioneers” for the exploration of mouse genetics leading
to the discovery of 127 separate loci with 63 genes
characterized so far (Silvers, 1979; Bennett and
Lamoreux, 2003; Oetting, 2005).
Among them, the three genes of the tyrosinase-
related family, namely, tyrosinase, Tyrp1 (Tyrosinase-
related protein 1) and Dct (Dopachrome tautomerase)
were also discovered by analysis of coat color mutants
(Haldane et al., 1915; Hertwig, 1942; Green, 1972). 103
spontaneous or induced phenotypic alleles have been
described for tyrosinase, and they result in albinism or
hypopigmentation due to absence or reduction of
melanin in homozygotes (Fig. 1) (Beermann et al., 2004;
Mouse Genome Database (MGD), 2005). For Tyrp1, 49
phenotypic alleles are known, and homozygous Tyrp1-
mutant mice show a brown coat color phenotype on a
non-agouti background instead of the wild-type black
color (Fig. 1) (Mouse Genome Database (MGD), 2005).
Three mutations and one targeted deletion have been
described at the Dct gene locus, resulting in a dark grey
coat color on a non-agouti black background (Fig. 1)
(Guyonneau et al., 2004; Mouse Genome Database
The pigment production machinery
In mammals, the production of the melanin pigment
is achieved in two cell types of distinct developmental
origins. The melanocytes of the skin, hair follicle, inner
Genetics of pigment cells:
lessons from the tyrosinase gene family
F. Murisier and F. Beermann
ISREC (Swiss Institute for Experimental Cancer Research),
National Center of Competence in Research (NCCR) Molecular Oncology, Epalinges, Switzerland
Histol Histopathol (2006) 21: 567-578
Offprint request to: Dr. Friedrich Beermann, ISREC (Swiss Institute for
Experimental Cancer Research), Chemin des Boveresses 155, CH-
1066 Epalinges, Switzerland. e-mail: firstname.lastname@example.org
Cellular and Molecular Biology
ear, choroid, iris and ciliary body originate from the
neural crest, whereas the cells of retinal pigment
epithelium (RPE) originate from the optic cup of the
developing forebrain (Fig. 2) (Mayer, 1973; Martinez-
Morales et al., 2004). The melanin is produced and
stored in specialized lysosome-related organelles called
melanosomes. The three members of the tyrosinase-
related family are involved in the process of
melanogenesis leading to the production of either
eumelanin (brown-black) or pheomelanin (yellow-red).
The first step of melanin production involves
tyrosinase (monophenol monooxygenase, EC 126.96.36.199)
which catalyses the transformation of tyrosine into
dopaquinone. In the eumelanin pathway, the
dopaquinone is then transformed into dopachrome. The
further transformation of this product involves Tyrp1
and Dct, which share about 40% amino acid identity
with tyrosinase, but display their own and distinct
catalytic capacities (Jackson et al., 1992). Dct
(Dopachrome tautomerase, EC 188.8.131.52) catalyses the
transformation of dopachrome to dihydroxyindole
carboxylic acid (DHICA) (Tsukamoto et al., 1992). The
role of Tyrp1 (5,6-dihydroxyindole-2-carboxylic acid
oxidase, EC 1.14.18.-) is more controversial since it acts
as a DHICA oxydase but also stabilizes tyrosinase
(Jimenez-Cervantes et al., 1994; Kobayashi et al., 1998;
Garcia-Borron and Solano, 2002). When Tyrp1 and Dct
functions are not impaired, the pigment produced is
black. Mutation of Tyrp1 induces the production of a
brown pigment (Bennett et al., 1990). The loss of Dct
leads to a dark grey color (Guyonneau et al., 2004). In
addition, Dct might influence the balance between
eumelanin and pheomelanin synthesis (Costin et al.,
Genomic structure and evolution of the tyrosinase-
The genomic structure of the tyrosinase-related
family suggests that it has evolved from one ancestral
tyrosinase gene. The duplication of this gene is probably
responsible for the emergence of a tyrosinase-related
gene. Tyrp1 and Dct are evolutionarily more closely
related to each other than to tyrosinase and thus they
might have themselves duplicated from the primitive
tyrosinase-related gene (Budd and Jackson, 1995; Sturm
et al., 1995). The first duplication event must have taken
place before the divergence of ascidians and vertebrates
since two members of the tyrosinase gene family are
found in Halocynthia roretzi (Sato et al., 1999) and in
Ciona intestinalis (Ensembl genome browser, 2005).
The second duplication event then occurred before the
divergence of fishes and mammals since the three
members of the family are found in Fugu (Takifugu
rubripes) (Camacho-Hubner et al., 2000, 2002),
Goldfish (Carasius auratus) (Peng et al., 1994; Sato et
al., 1999) or Zebrafish (Danio rerio) (Kelsh et al., 2000;
Page-McCaw et al., 2004; Ensembl genome browser,
In the mouse genome, the 5 exons of the tyrosinase
Gene regulation in the tyrosinase family
Fig. 1. Coat color phenotypes in mice
(nonagouti, a/a) resulting from spontaneous or
targeted mutations in the tyrosinase-related
family genes. (A) wild-type black mouse, (B)
Tyrcalbino mouse, (C) Tyrp1bbrown mouse
and (D) Dcttm1(cre)Beedark grey mouse.
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Accepted December 7, 2005
Gene regulation in the tyrosinase family