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Posttranscriptional Regulation of the Neurofibromatosis 2 Gene

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Neurofibromatosis type 2 NF2 is associated with a homozygous inactivation of the neurofibromatosis 2 NF2 gene. Despite intense study of the NF2 gene, the mechanism by which the NF2 tumor suppressor acts to prevent tumor formation is not well understood. The goal of this research is to examine the role of posttranscriptional regulation of the NF2 gene. With this grant support, we have confirmed that vestibular schwannomas express a distinct pattern of alternatively spliced NF2 transcripts lacking specific exons. Analysis of NF2 expression during embryonic development reveals that NF2 is an early expression marker. Strong NF2 promoter activity was seen in the embryonic ectoderm and in all NF2-affected tissues examined. Importantly, we observed strong NF2 promoter activity in the developing brain and in sites containing migrating cells including the neural tube closure and branchial arches. Furthermore, we noted a transient change of NF2 promoter activity during neural crest cell migration. The NF2 promoter expression pattern during embryogenesis suggests a specific regulation of the NF2 gene during neural crest cell migration and further support the role of merlin in cell adhesion, motility, and proliferation during development. By using the conditional gene targeting approach, we have generated an Nf2flox8 allele. Transgenic and conditional knockout mice have been generated to address whether the alternative splicing NF2 isoform with exon 8 deletion preferentially expressed in schwannomas possess any additional properties conducive to tumor formation in vivo. Also, we show that the 3 UT sequence of the NF2 gene does not affect the stability of NF2 RNA or the efficiency of protein translation in vitro. Utilizing the vestibular schwannoma samples procured from this study, we have established a quantifiable human vestibular schwannoma xenograft model in SCID mice and identified cyclin D3 as a growth-promoting factor for vestibular schwannomas.

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  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research

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