Graduate Programs in the Life Sciences

Research Focus

Dr. Schimenti's laboratory uses the laboratory mouse as a model system to investigate the genetics of mammalian development, gametogenesis, and maintenance of genome integrity. They use a variety of technologies to mutagenize the mouse genome to identify novel genes involved in these processes. With respect to gametogenesis, they concentrate on the process of meiosis. During meiosis, DNA is replicated, homologous chromosomes pair, recombination occurs, and two rounds of divisions follow to create haploid gametes. They have isolated several mutants that disrupt these steps, using chemical mutagenesis of embryonic stem (ES) cells and of the germline. One of them is called Mei1, which disrupts the process of chromosome synapsis (intimate pairing of homologous chromosomes). They found that Mei1 is required for the genetically-programmed induction of double strand breaks in meiotic chromosomes, which is the initiating event in recombination. Despite being required for such a fundamental process, this gene is unique to vertebrates. Another meiotic mutation they are studying is called mei4. This abolishes the formation of chiasmata, the sites of crossing over. In addition to their collection of meiotic mutants, they are investigating infertility mutations that affect earlier stages of germ cell production as well as postmeiotic sperm development.

In another project, a region-specific ENU mutagenesis screen was conducted to explore the functional content of proximal mouse Chromosome 5, representing about 2% of the genome. Embryonic lethal mutations (a total of 37) were overwhelmingly the largest class of mutants recovered. They have determined the timing and phenotypes of death for most of them, which range from pre-implantation lethality to a late-gestation homeotic-like skeletal transformation. To facilitate the mapping and cloning of these mutations in a systematic manner, they created a collection of nested chromosomal deletions in the region, using an ES cell-based technology. Failure of a deletion to complement a lethal mutation indicates the location of the defective gene.

A more recent project involves the isolation of mice having mutations causing genomic instability (GIN). GIN is a hallmark of cancer cells, but there is controversy over whether it is an early or late event or cancer progression. By isolating a collection of GIN mutants, they hope to address this issue and to potentially identify new cancer susceptibility genes. A mutagenesis screen was conducted for mice with GIN, using a flow cytometric screen for DNA fragmentation in blood cells. Of the two mutations that they've positionally cloned, one is polymerase theta (Polq), which appears to play a rather unique role in DNA repair. By placing this mutation into certain genetic backgrounds, tumor progression is either accelerated or delayed. The other is an allele of a DNA replication control gene, causing a 20 fold elevation in chromosome aberrations. Recent data indicates that mice with this mutation are highly susceptible to mammary tumors.