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The role of apc tumor suppressor gene in development and tumorigenesis of the central nervous system - the conditional gene inactivation approach


Research objectives and content
Germline mutations of the Apc tumor suppressor gene cause FAP (Familial Adenomatous Polyposis), a rare hereditary colorectal cancer syndrome and somatic mutations of Apc occur in the great majority of sporadic colorectal tumors. Recent studies have demonstrated that the Apc protein is expressed in most tissues during the mouse development and in adult animals. As an example, Apc is highly expressed in post mitotic neurons in specific brain areas, such as the cerebellum during development. An interesting correspondence to these findings is that a considerable percentage of patients with FAP develop also medulloblastomas, a highly malignant embryonic tumor of the cerebellum. The role played by Apc in this different context is still unclear.
To date, the available mouse models, such as the Apc Min mouse and the conventional knock out are not suitable to address these questions. In both cases the heterozygous die in the first months of life as a consequence of the intestinal tumors and the homozygous mutants are embryonic lethal. In order to study the effects of selective inactivation of Apc in vivo we are generating conditional Apc mouse mutants using the Cre/LoxP site specific DNA recombination system. LoxP sites are being introduced in intron 1 and 2 kb downstream to the polyA tail of the Apc gene via homologous recombination in ES cells. ES cell clones with the targeted Apc lox alleles will be used to generate conditional mouse mutants. These mice will be crossed with transgenic mouse strains expressing the Cre recombinase in a tissue specific fashion. Training content (objective, benefit and expected impact)
The potential of transgenic technologies for the advancement of medical science is playing a crucial role in narrowing the gap between scientists engaged in basic molecular science and clinicians and increasingly encouraging clinical researchers to use these new tools. Therefore we think that a permanence of the applicant in a laboratory with such qualified experience in mouse molecular genetics will lead to the acquisition of modern molecular biological techniques and also to a general experience in planning and developing a scientific project. The applicant's expertise in histopathological analysis of genetically modified animals will be. on the other hand, a gain of expertise for the host laboratory.
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121,plesmanlaan 121
1066 CX Amsterdam

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