Genomic structure and evolutionary conservation of the tyrosinase gene family from Fugu

Friedrich Beermann
2002
Article

The tyrosinase gene family encompasses three members, tyrosinase, tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct), which encode for proteins implicated in melanin synthesis. In human and mouse, genomic organization is known for all three genes, revealing common features of regulatory elements and of exon/intron structure. We have set out to identify the complete family from a more primitive vertebrate, the pufferfish Fugu (Takifugu rubripes), which is characterized by a compact genome. We had recently isolated and characterized the Fugu tyrosinase gene (Genesis 28 (2000) 99-105). We now report the isolation and characterization of the two other members of the family, Tyrp1 and Dct. Regulatory sequences from these genes function in mouse pigment cells and are able to mediate reporter gene expression. Our results demonstrate the existence of all three tyrosinase family members in teleosts and underline the evolutionary conservation of the pigmentary system.

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Friedrich Beermann
2002
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https://infoscience.epfl.ch/record/115147?ln=fr

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Souris

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Expression génétique

L'expression des gènes, encore appelée expression génique ou expression génétique, désigne l'ensemble des processus biochimiques par lesquels l'information héréditaire stockée dans un gène est lue po

Tyrosinase

La tyrosinase (ou catéchol oxydase ou monophénol monooxygénase) est une oxydoréductase qui catalyse l'oxydation des phénols, comme la tyrosine : : : : Cette enzyme intervient dans deux réactions di

The mouse c locus encodes tyrosinase (monophenol monooxygenase; monophenol, L-dopa:oxygen oxidoreductase, EC 1.14.18.1), the key enzyme in melanin synthesis, which is expressed in the pigment epithelium of the retina and in melanocytes derived from the neural crest. To define regulatory regions of the gene that are important for cell type-specific expression, a deletion series of the tyrosinase 5' region was fused to a chloramphenicol acetyltransferase (CAT) reporter gene and electroporated into tyrosinase-expressing and -nonexpressing cell lines. We show that 270 base pairs 5' of the transcriptional start site is sufficient for CAT expression in a human and a mouse melanoma cell line. This 5' flanking fragment, when cloned in the context of a tyrosinase minigene construct and injected into fertilized eggs of an albino mouse strain, is sufficient for cell type-specific expression in mice. The transgenic mice were pigmented in both skin and eyes. In situ hybridization analysis shows that the 270-base-pair regulatory region contains elements sufficient for specific expression of the transgene both in the pigmented epithelial cells of the retina, which are derived from the optic cup, and in neural crest-derived melanocytes.

1991

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The mouse tyrosinase gene. Promoter modulation by positive and negative regulatory elements

Friedrich Beermann

Tyrosinase, the key enzyme in melanin synthesis, is expressed specifically in pigment-producing cells. Studies with transgenic mice and gene transfer experiments have demonstrated that the 270-base pair 5'-flanking sequence of the mouse tyrosinase gene leads to weak but cell type-specific and developmentally regulated expression. To elucidate the underlying transcriptional control, we focused on the identification of cis-acting elements within this 270-base pair minimal promoter. We also addressed the potential role of promoter elements in the control of cAMP regulation of the tyrosinase gene. Deletion and linker scanning mutagenesis revealed that promoter activity is modulated by two positive elements and one negative element. One of the positive elements includes the M-box, a sequence motif shared with the promoter of two other melanocyte-specific genes, trp-1 and trp-2. Cotransfection experiments provide evidence that a basic helix-loop-helix-zipper protein, encoded at the microphthalmia gene locus, transactivates the tyrosinase promoter, probably by binding to the M-box. Activating cis elements are bound by nuclear factors in vitro and confer increased expression to a reporter gene both in melanoma cells and in fibroblasts. We therefore suggest that the positive promoter elements modulate tyrosinase expression rather than determine cell specificity in vivo, whereas the negative element acts cell type specifically.

1994

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Regulation of the tyrosinase promoter in transgenic mice: expression of a tyrosinase-lacZ fusion gene in embryonic and adult brain

Friedrich Beermann

The enzyme tyrosinase is indispensable for pigmentation and the gene is expressed mainly in pigment cells. Regulatory elements, at -12 to -15 kb (enhancer) and within the 270 bp directly upstream of the transcription start site, have been described recently and their importance demonstrated in transgenic experiments. We were interested in tyrosinase promoter activity during development and used beta-galactosidase as reporter gene. Transgenic mice were generated carrying a tyrosinase-lacZ fusion gene, containing 6.1 kb of tyrosinase 5' sequences. In transgenic embryos, beta-galactosidase activity was detected along the entire neural tube, with the most prominent expression in the developing telencephalon, and also in the adult brain. Equivalent expression was observed in the developing retina. Tyrosinase protein was identified in embryonic and adult brain, but no DOPAoxidase or tyrosine hydroxylase activity was detected. From our results we conclude that 1) tyrosinase protein is present in embryonic and adult mouse brain and 2) the tyrosinase promoter can direct expression of a reporter gene to pigment cells and neural tissues.

1997

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