Transgenic laboratory animals in gene regulation research

Abstract

The knowledge of how genes are regulated in mammals has increased enormously since the development of the first transgenic mice in the early 19805. Up to then, studies of gene regulation were carried out in cultured cell lines. The advantages
of investigating gene regulation in transgenic animals as opposed to cell culture systems. are manifold, e.g, allowing the study of expression of the transgene in every cell type and in relation to development.
The term gene regulation implies that genes, present in all cells in the body. are directed to expression in specific cell types, at a specific level and at a developmentally correct time. This is brought about by the influence of DNA regions flanking
the individual genes. Thus, the tissue specificity of a gene is defined by the surrounding DNA regions.
Some of the types of DNA regions which are responsible for the expression pattern of a specific gene, are named promoters and enhancers. The promoter is positioned in front ofthe gene close to the transcription start site. and is responsible for
correct transcription initiation. The enhancer strongly enhances the transcription from the promoter, and is able to do so regardless of its position and orientation. Consequently, the enhancer can be positioned in front of. behind or within the
gene which it regulates. Both promoters and enhancers are able to bind transcription factors, which are proteins that by binding to DNA. take part in gene regulation.
In recent years, studies carried out in transgenic mice have made it possible to identify new types of control regions in addition to promoters and enhancers. Thus. the locus control regions (LCR) from the human B-like globin locus is able to confer tissue specific. position independent expression of human B-globin genes in transgenic mice. It is likely that LCRs from different genes will become important in gene rgulation studies in transgenic mice, as position independent expression of transgenes may be obtained by including an LCR in the microinjected construct. However, so far LCRs have been characterized in only a small number of genes.
Individual transgenic mice produced by microinjection carrying identical transgenes, express the transgenes at highly varying levels, depending on the site in the genome at which the transgene has integrated. This is clue to the position~effect, that is, the expression of the integrated transgene is influenced by the surrounding DNA. Hopefully, in the future, a better understanding of the mechanisms causing the position-effect, will lead to the development of vector»systems that allow transgene expression which is independent of the site of integrations.