Generation Of A Mouse Model For Schwannomatosis
Annual rept. 1 Sep 2009-31 Aug 2010
NATIONWIDE CHILDREN'S HOSPITAL COLUMBUS OH RESEARCH INST
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Recent molecular genetic studies suggest a four-hit hypothesis involving inactivation of both the INI1SNF5 and NF2 tumor suppressor genes in the formation of schwannomatosis-associated tumors. To generate a mouse model for schwannomatosis, we have proposed to simultaneously inactivate both Ini1Snf5 and Nf2 in NF2-expressed tissues. Toward achieving this goal, we have produced five lines of transgenic NF2CreER mice carrying a 2.4-kb NF2 promoter driven a CreER expression unit. To prove the utility of the inducible CreER system, we generated NestinCreERNf2flox2flox2 mice. By tamoxifen injection, we inactivated Nf2 in neuroprogenitor cells at various times during embryonic development. We found that Nf2 is essential for neurulation and neuroepithelial progenitor proliferation during mammalian brain development. In contrast, mice with Nf2 inactivation during mid-to-late gestation efficiently developed schwannomas, suggesting that NestinCreERNf2flox2flox2 mice may serve as an alternative model for NF2-associated schwannomas. By mating NF2CreER mice with Nf2flox2flox2 mice, compound NF2CreERNf2flox2flox2 mice were produced. Like NestinCreERNf2flox2flox2 mice with Nf2 inactivation during mid-to-late gestation, an NF2CreERNf2flox2flox2 mouse developed a schwannoma at about one year of age, suggesting that this mouse line expresses functional CreER activity. In addition, by mating NF2CreER mice with Snf5floxflox mice, we generated NF2CreERSnf5floxflox mice for further analysis.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research