Melanocytes and Pigmentation Are Affected in Dopachrome Tautomerase Knockout Mice

Abstract

The tyrosinase family comprises three members, tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), and dopachrome tautomerase (Dct). Null mutations and deletions at the Tyr and Tyrp1 loci are known and phenotypically affect coat color due to the absence of enzyme or intracellular mislocalization. At the Dct locus, three mutations are known that lead to pigmentation phenotype. However, these mutations are not null mutations, and we therefore set out to generate a null allele at the Dct gene locus by removing exon 1 of the mouse Dct gene. Mice deficient in Dct [Dct^tm1(Cre)Bee] lack Dct mRNA and dopachrome tautomerase protein. They are viable and do not show any abnormalities in Dct-expressing sites such as skin, retinal pigment epithelium, or brain. However, the mice show a diluted coat color phenotype, which is due to reduced melanin content in hair. Primary melanocytes from Dct knockout mice are viable in culture and show a normal distribution of tyrosinase and tyrosinase-related protein 1. In comparison to the knockout, the slaty mutation (Dct^slt/Dct^slt) has less melanin and affects growth of primary melanocytes severely. In summary, we have generated a knockout of the Dct gene in mice with effects restricted to pigment production and coat color.

Thanks are due to Christelle Richard, Barbara Canepa, and Julien Ackermann for help with blastocyst injections, genotyping, RNA analyses, and melanocyte cultures; Ian Jackson and Peter Budd for supplying genomic clones of mouse Dct; the MIM facility for help with histology and immunofluorescence; Lynn Lamoreux for providing Dct^slt mice; and to Edith Hummler for precious advice on ES cell work and comments on the manuscript.

The present work was supported by grant 3100-066796.01 (F.B.) from the Swiss National Science Foundation and by the National Center of Competence in Research Molecular Oncology, a research instrument of the Swiss National Science Foundation.