Construction of an NF2 Mutant Mouse: Towards an Animal Model of Neurofibromatosis Type 2.
Final rept. 22 Sep 93-21 Sep 96,
MASSACHUSETTS INST OF TECH CAMBRIDGE
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Neurofibromatosis type 2 NF2 is a hereditary disorder featuring the development of nervous system tumors, particularly schwannomas. The tumor suppressor responsible for NF2 is a member of a class of cytoskeletal-associated proteins, and therefore represents a new type of tumor suppressor. In an effort to develop an animal model for NF2 and investigate the function of the NF2 gene product merlin, we have employed gene targeting to create a mouse that is mutant at the Nf2 locus. Nf2 heterozygous mice are predisposed to developing a broad spectrum of tumor types which show LOH at the Nf2 locus. Our results also demonstrate strong cooperation between mutations at the Nf2 and p53 or Nf1 loci in the development of specific tumor types. We have also determined that Nf2 is required at multiple stages of development. Nf2 homozygous mutant embryos fail to initiate gastrulation, apparently due to a defect in the extraembryonic lineage. The generation of chimeric embryos partially composed of Nf2 homozygous mutant cells that are marked by the lacZ transgene reveals several additional stages of development during which merlin function is essential. Together studies of the consequences of merlin loss during both development and tumorigenesis in the mouse will greatly enhance our understanding of the consequences of merlin loss in human disease.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research