IL-22 The mouse tyrosinase gene: structural and functional studies in transgenic mice.

The mouse tyrosinase gene, encoding the rate-limiting enzyme in the melanin synthesis pathway, was assigned, in 1990, to the c (albino ) locus by classical rescue experiments driven by functional constructs in transgenic mice. These pioneer reports triggered the study of the regulation of endogenous tyrosinase gene expression by combining different amounts of upstream regulatory and promoter regions and testing their function in vivo in transgenic animals. Indeed, the expression studies on the mouse tyrosinase gene regulation have eventually become an example and, possibly, a paradigm of how a representative mammalian expression domain could be organized within the nuclear chromatin, and how a gene establishes its specific pattern of expression during development and throughout the life of an organism. Correct and reproducible tyrosinase transgenic expression was not achieved in the initial studies. In contrast, faithful tyrosinase transgenic expression was reported when the entire expression domain was transferred to the germ-line of mice using artificial-chromosome-type transgenes. The use and modification of these large tyrosinase transgenic constructs enabled the discovery of previously unknown but fundamental regulatory regions, such as the tyrosinase locus control region (LCR), whose presence was required in order to guarantee position independent and copy number dependent-expression of tyrosinase transgenes, with an expression level, per copy, comparable to that of an endogenous wild-type allele. Subsequently, functional dissection of regulatory elements present within this LCR through the generation of new artificial-chromosome type tyrosinase transgenes have revealed the existence of different regulatory activities, including the description of a novel boundary element. New in vivo and in vitro studies have contributed to establish the relevance of the regulatory elements associated with the mouse tyrosinase expression domain. The presence of some of these elements has also been identified in other mammalian species by genome comparison analysis, thus indicating the evolutionary importance of their presence in tyrosinase genes (and transgenes). [ABSTRACT FROM AUTHOR]