The availability of DNA sequence for the human and mouse has heralded a new era in biology. These data are yielding structural details for all human and mouse genes. Our ability to interpret and use these data is dependent on our ability to assess gene function within a whole organism, which is typically done through the study of gene mutations. For the study of human disease, especially those of the blood, the mouse constitutes a premier model. In the mouse, it is possible to induce random point mutations in the germline using ethyl nitrosourea (ENU). ENU mutagenesis of mice followed by screens for specific phenotypes allows for the isolation of strains bearing single gene mutations that cause deviation from normal function. This, coupled with robust approaches to mutant gene identification, allows the identification of genes that regulate complex biological processes. Because the mutations are single base pair changes, the alleles generated are very often partial loss of function alleles, and thus no redundant allele series are possible, which can give a wealth of information about gene function. In addition, gain-of-function alleles are also possible. The power of ENU mutagenesis is entirely dependent on the sensitivity and specificity of the phenotypic screen. We propose the development of mouse strains that will allow one to screen for mutants that are altered in particular blood cell compartments. We are interested in the homeostatic mechanisms that regulate hematopoietic stem cell number and commitment to differentiation. This is a complex process that is under genetic control. Indeed, it has been possible to identify variability in stem cell number among mouse strains and to map several influential genes, but as of yet, no specific genes that regulate stem cell number have been identified. The approaches described thus far are hampered by major problems including the laborious nature of screens for blood cell number and function. We intend to generate strains of reporter mice that will allow the enumeration of a specific blood cell lineage compartment through analysis of mouse serum. The establishment of such strains will allow one to screen for mutants that have abnormal hematopoiesis.
