Transgenic Mouse Technology in Skin Biology: Generation of Complete or Tissue-Specific Knockout Mice

Abstract

Many human skin diseases are caused by gene mutations that result in either the loss of protein or an altered protein function. To understand how these mutations cause disease and to find possible therapeutic targets, it is crucial to use not only cell culture approaches but also in vivo investigations in a complex multicellular organism to assess the contributions of the macroand microenvironment. Although clinical data provide a wealth of information on disease-causing mutations, it is often difficult to distinguish between cause and consequence in humans. The genetic and environmental variation is another complicating factor in understanding the underlying mechanisms that result in disease. Targeted genetic modifications in related mammals therefore offer great possibilities to investigate molecular mechanisms that underlie mammalian physiology and disease. The mouse is one of the most relevant research organisms because it shares 99% genetic identity with humans, inbred strains exist, and it has been very well characterized on both the genetic and behavioral levels (Paigen, 2003). Most importantly, the groundbreaking work of Mario Capecchi, Martin Evans, and Oliver Smithies in the 1980s, in which they discovered how to introduce specific gene modifications in mice using embryonic stem cells, opened the way to address directly the consequences of specific mutations. For this they received the Nobel Prize in Physiology or Medicine in 2007 (Vogel, 2007). We provide an overview of how to design (conditional) knockout mice and discuss their relevance for understanding human disease.