Stem Cell Regulation by the NF2 Tumor Suppressor Merlin

描述(申请人提供)：干细胞维持在成人体内的微环境中，调节这些细胞的分化和增殖。干细胞在癌症发展中的作用知之甚少，但在正常生物学和癌症生物学中至关重要。我们的初步观察表明，在体内消融NF2肿瘤抑制因子Merlin在皮肤中可以改变正常的表皮发育。因此，我们假设Merlin对于上皮干细胞的正常调节是必需的。我们的长期目标是：1)确定Merlin在调节表皮干细胞隔间中的作用。2)确定Merlin是否在表皮干细胞巢中组织膜受体信号。3)确定Nf2缺乏是否促进表皮肿瘤的发生。我们已经培育出了专门从小鼠皮肤中删除Nf2基因的小鼠。除了分子方法外，我们还将利用这些小鼠来研究Merlin在干细胞室中的作用。这些研究将有助于我们理解NF2肿瘤抑制因子如何调节细胞间的相互作用，特别是干细胞与周围生态位之间的相互作用，以及这些相互作用在肿瘤发生和发展为转移性癌症中所起的作用。

DESCRIPTION (provided by applicant): Stem cells are maintained within the adult body in microenvironments that regulate both the differentiation and proliferation of these cells. The role that stem cells have in cancer development is poorly understood but critically important in normal and cancer biology. Our preliminary observations indicate that in vivo ablation of the Nf2 tumor suppressor, Merlin in the skin alters normal epidermal development. Therefore we hypothesize that Merlin is required for normal regulation of epithelial stem cells. Our long term objectives are: 1)To determine the role of Merlin in regulation of the epidermal stem cell compartment. 2)To determine whether Merlin organizes membrane receptor signaling in the epidermal stem cell niche. 3)To determine whether Nf2 deficiency promotes epidermal tumorigenesis. We have generated mice specifically deleting the Nf2 gene from mouse skin. We will utilize these mice in addition to molecular approaches to investigate the role of Merlin in the stem cell compartment. These studies will contribute to our understanding of how the Nf2 tumor suppressor regulates cell-cell interactions specifically between stem cells and the surrounding niche and the role these interactions have in tumor development and progression into metastatic cancer.