The research of the Unit on Molecular Genetics focuses on the development and function of the mammalian central nervous system, using the generation and study of mouse mutants as a major approach. The importance of mouse mutants to the study of mammalian development and function has two complementary aspects: First, mouse mutants lacking specific genes allow the testing of hypotheses about the roles of these genes. Second, mouse mutants with overt phenotypes can be studied to provide fundamental insights into biological processes. In this project we are systematically scanning for overt informative phenotypes in new mouse mutants produced by introduction of a series of deletions spanning large regions on mouse chromosomes. Deriving new informative mouse mutants presents a problem. We have undertaken a comprehensive long-term project to scan for new mutations by engineering a series of specific deletions spanning mouse chromosomes syntenic to the Down syndrome consensus region of human chromosome 21. There are two requirements for the success of this approach: a) integrated gene maps with the locations, sequences, and expression patterns of genes in large chromosomal regions are necessary to define the genes within each deletion, and b) a method for efficiently introducing specific, large deletions into the mouse germline. Using the hybridization-based approach of direct cDNA screening developed by our group, we identified a number of """"""""anonymous"""""""" genes from the Down Syndrome Consensus region of human chromosome 21. We are now extending these studies towards testing whether these genes result in overt mouse phenotypes by developing a systematic method for engineering deletions using the Cre/lox site-specific recombination system. We have begun introducing lox sites at specific loci on mouse chromosome 10 which are syntenic to part of the Down Syndrome Consensus region on human chromosome 21.
