| The Schimenti laboratory uses
the laboratory mouse as a model system to investigate the genetics of
mammalian development, gametogenesis, and maintenance of genome integrity.
The lab has used forward genetic screens to identify novel genes involved
in these processes. With respect to gametogenesis, the focus is 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. Mutants isolated in the Schimenti lab disrupt
various steps in these processes. These mutants were produced by chemical
mutagenesis of embryonic stem (ES) cells and of the germline. Some of
lab's advanced studies focus on mutations that are involved in
recombination initiation (the formation of double strand breaks), strand
exchange during recombination, sister chromatid cohesion, the formation of
chiasmata, and transcriptional control of meiotic genes. In addition to
this collection of meiotic mutants, the lab investigates 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. The timing and phenotypes of death have been
determined 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, a
collection of nested chromosomal deletions in the region was created,
using an ES cell-based technology. Mice bearing some of these deletions
provide a mouse model for the Wolf-Hirshhorn contiguous gene syndrome in
humans.
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, the lab plans 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 were positionally
cloned, one is in the gene encoding polymerase theta (Polq), an enzyme
which is involved in translesion synthesis and may be required for somatic
hypermutation of immunoglobulin genes. The other mutation is in a
hypomorphic allele of the DNA replication licensing gene Mcm4, causing a
dramatic elevation in chromosome instability. Remarkably, these mutant
mice are highly susceptible to mammary adenocarcinomas.  |
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