Targeted Conditional Somatic Mutagenesis in the Mouse: Temporally-Controlled Knock Out of Retinoid Receptors in Epidermal Keratinocytes

Abstract

This chapter focuses on the use of animal models to study nuclear receptor function. The activity of nuclear receptors as the regulators of transcriptional responses is controlled by classic hormones and the derivatives of vitamin and dietary nutrients, including fatty acids and cholesterol derivatives, with the possible exception of the so-called orphan receptors for which no ligands have been yet identified. Nuclear receptors are now seen as the integrators of multiple signals and are thought to be involved in the control of most complex processes in metazoans. The chapter illustratesthe ways conditional mutagenesis approach allows revealing the precise physiological role of nuclear receptors in a given adult tissue. The epidermis—a stratified epithelium made principally of keratinocytes—is a highly dynamic structure. The innermost basal layer that is attached to the basement membrane is a proliferative layer, from which keratinocytes periodically withdraw from the cell cycle and commit to terminally differentiate, while migrating outward into the next layers known as the “spinous and granular layers,” which together represent the suprabasal layers. An obvious limitation to the use of somatic mutagenesis is to determine the function of gene products in a given cell type, whenever the gene mRNA and/or the protein products have a long half-life as compared to that of the cell.