Schwann Cells in Neurofibromatosis Type 2 (NF2)

描述(申请人提供)：大约10%的颅内肿瘤是神经鞘瘤，这是一种由双等位基因NF2突变的雪旺细胞组成的良性肿瘤。NF2突变或缺失被认为是导致神经鞘瘤形成的原因。有几条证据表明，NF2蛋白Merlin参与了小G蛋白的信号传递。生化证据和我们对原代神经鞘瘤细胞的分析表明，Merlin在RAC信号转导中发挥作用。正常雪旺细胞是极化的，一个表面附着在轴突上，另一个表面附着在基底板上，而神经鞘瘤细胞与轴突无关。这种极性的丧失很可能是RAC信号改变的次要原因。由于Rac信号通路与雪旺细胞的相关性尚不清楚，我们建议评估Merlin-Rac级联信号通路在雪旺细胞生长和肿瘤发生中的作用。我们的具体假设是，Merlin限制了雪旺细胞中RAC信号的持续时间。我们进一步假设RAC信号失控是神经鞘瘤失败的轴突-神经胶质细胞相互作用的原因。我们计划使用功能获得和功能丧失的小鼠模型和来自人类神经鞘瘤的原代细胞的组合来检验这些假设。我们认为，对原代神经鞘瘤细胞的分析为研究早期人类癌细胞的纯群体提供了难得的机会。这项拟议的研究有望为正常轴突-神经胶质相互作用的调节提供洞察力，并导致了解并最终治疗人类神经鞘瘤的策略。

DESCRIPTION (provided by applicant): About 10% of all intracranial tumors are schwannomas, benign tumors comprised of Schwann cells with biallelelic NF2 mutations. NF2 mutation or loss is believed to cause schwannoma formation. Several lines of evidence implicate merlin, the NF2 protein, in small G-protein signaling. Biochemical evidence and our analysis of primary schwannoma cells suggest that merlin functions in Rac signaling. While normal Schwann cells are polarized, with one surface attached to axons and the other to basal lamina, schwannoma cells are unassociated with axons. This loss of polarity is likely to arise secondary to altered Rac signaling. Because the relevance of the Rac signaling pathway to Schwann cells is not known, we propose to evaluate a merlin-Rac cascade in Schwann cell growth and tumorigenesis. Our specific hypothesis is that merlin limits the duration of Rac signaling in Schwann cells. We further postulate that deregulated Rac signaling accounts for the failed axon-glial interactions characteristic of schwannomas. We plan to use a combination of gain-of-function and loss-of-function mouse models and primary cells from human schwannomas to test these hypotheses. We believe that analysis of primary schwannoma cells offers a rare opportunity to study a pure population of early stage human cancer cells. The proposed studies are expected to provide insight into regulation of normal axon-glial interactions, and to lead to strategies to understand and ultimately treat human schwannomas.