GENE TARGETING IN EMBRYONIC STEM-CELLS - THE NEW PHYSIOLOGY AND METABOLISM

The development of transgenic technology, whereby genes (or mutations) can be stably introduced into the germline of experimental mammals, n ow allows investigators to create mice of virtually any genotype and t o assess the consequences of these mutations in the context of a devel oping and intact mammal. In contrast to traditional ''gain-of-function '' mutations, typically created by microinjection of the gene of inter est into the one-celled zygote, gene targeting via homologous recombin ation in pluripotential embryonic stem cells allows one to modify prec isely the gene of interest. The purpose of this review is to introduce the reader to the history of development of embryonic stem cell techn ology, the current methods employed to create ''knock-out'' mice, and the application of these methods to solve problems in biology. While t he technology promises to provide enormous insight into mammalian deve lopment genetics, our desire is that this review will stimulate the ap plication of gene targeting in embryonic stem cells to begin to unrave l problems in complex regulatory pathways, specifically intermediary m etabolism and physiology.