Genetic, molecular and phenotypic analysis of the l(7)1Rl region in mouse chromosome 7

l(7)1Rl is an early post-implantation lethal mutation identified by Dr. Liane Russell through complementation analyses among the pink-eyed-dilution locus-deletion mutations (Russell et al., 1995). Studies in this dissertation determined that the lethality of l(7)1Rl mutation occurs at peri-implantation stages. l(7)1Rl homozygous embryos initiate the implantation process, but fail to develop egg-cylinder structures, and die at around E4.5 - E5.5. Genetic and molecular tools were utilized in this study to characterize the chromosomal interval encompassing the l(7)1Rl functional unit. A novel gene, Ihw (Included in Human WAGR region), was cloned from the proximal deletion breakpoint of one l(7)1Rl mutation,p^8FDFoD. An integrated deletion/physical map was constructed for the chromosomal interval between Ihw and p. This map defined the minimum critical region for the l(7)1Rl functional unit; in addition, it defined further the proximal deletion breakpoints for 15 of the l(7)1Rl mutations. The set of DNA clones that span the interval are therefore valuable resources for cloning and characterizing the genes for l(7)1Rl as well as other genes within that interval. The potential biological function of Ihw was also investigated. Ihw is specifically expressed in the central nervous system in mice, and its human homolog maps to human chromosome 11p14.3 and is deleted in some of the WAGR (Wilms' tumor, Aniridia, Genitourinary abnormality, and Mental retardation) patients. Ihw mutations are therefore proposed to contribute to the mental retardation in WAGR patients. In order to investigate further the biological function of Ihw, a gene-targeting experiment was carried out to generate Ihw^-/- knockout mice in which exon 1 of the Ihw gene would be disrupted. This last study is still in progress at the time this dissertation is written. Studies in this dissertation also determined that the chromosome interval between Gas2 and Ihw in mouse chromosome 7 is homologous to human chromosome 11p14.3 - 11p15.1. p-region mutations in that interval are therefore good animal models to study human diseases mapped to 11p14.3 - 11p15.1.