Discovery and functional characterisation of new genes by large scale ENU mutagenesis in mice

The most important tool to obtain insight into the function of genes is the use of mutant model organisms. Homologous recombination in embryonic stem cells allows the systematic production of mouse mutants for any gene that h as been cloned. Gene trap strategies have been designed to interrupt even u nknown genes which are tagged by the inserted vector and can be characteriz ed structurally and functionally. Complementary to such 'gene-driven' appro aches, 'phenotype-driven' approaches are necessary to identify new genes or gene products through a search for mutants with specific defects, e.g. in immune function and resistance to infectious diseases. Mutagenesis using th e alkylating agent N-ethyI-N-nitrosourea (ENU) is a powerful approach for t he production of mouse mutants (mainly point mutations). ENU mutagenizes - among other cells - premeiotic spermatogonia of F0 males which can be bred to produce a large number of G1 offspring or G3 pedigrees, respectively. It has been demonstrated for certain loci that the Frequency of mutant recove ry is about 1/1000 (recessive mutation) or 1/5000 (dominant mutation) far a specific locus that can be scored phenotypically, although strain as well as dosage and treatment regime do influence the mutagenesis rate. The mutan ts produced will be mainly hypomorphic, although gain-of-function and compl ete loss-of-function mutants can also be expected. These mutants are import ant tools for the identification of candidate genes for animal health, offe ring new strategies for the prevention, diagnosis, and therapy of diseases.