NEURONAL AND LYMPHOID LTK PROTEIN KINASE

我们克隆了一种极不寻常的细胞生长新成员 分化控制受体酪氨酸激酶家族，称为ltk， 它在成年小鼠前脑神经元和Pre-B中特异表达 淋巴细胞。因为LTK很可能控制重要的信令 途径，我们提出的对该受体的进一步分析可能不会 不仅提高了对淋巴和神经元生物学的理解，而且 提供有关神经元和淋巴系统疾病原因的线索。这个 我们建议的研究的具体目标是： 1.证实淋巴和神经元Ltk cDNAs预测蛋白质与 很大程度上不同的胞外结构域。这个史无前例的发现 提示ltk可能是不同淋巴和神经元的受体。 配基。我们还将扩展我们的发现，淋巴Ltk不是 在转基因细胞表面表达。我们将这种缺乏归因于 表面表达到缺少一个必要的亚基，导致 不正确的受体组装。我们将测试转基因神经元 Ltk是细胞质的，以及额外的淋巴和神经元cDNA 恢复表面表达Ltk。 2.分析ltk发挥作用的信号通路，通过创建 通过ES细胞基因打靶获得ltk基因缺陷小鼠。这些老鼠可能会揭示 无论淋巴Ltk是前B细胞生长的受体还是 分化因子。这种因子可能是一种有用的治疗剂。 治疗B细胞恶性肿瘤。如果我们关于ltk控制的推测假说 细胞存活是正确的，ltk缺陷小鼠可能表现为进展性 神经退行性变并提供人类神经退行性变的线索 精神错乱。 3.利用ltk的高表达，鉴定核因子 可能控制淋巴细胞和神经元的重要方面 发展。这项工作可能导致对启动子元件的鉴定 使有丝分裂后大脑神经元靶向基因表达 转基因动物。

We have cloned a highly unusual new member of the cell growth and differentiation controlling receptor tyrosine kinase family, called ltk, which is specifically expressed in adult mouse forebrain neurons and pre-B lymphocytes. Because ltk is likely to control important signalling pathways, the further analysis of this receptor as proposed by us may not only improve the understanding of lymphoid and neuronal biology, but also provide clues about causes of neuronal and lymphoid disorders. The specific aims of our proposed research are: 1. To confirm that lymphoid and neuronal ltk cDNAs predict proteins with largely different extracellular domains. This unprecedented finding suggests that ltk may be the receptor for different lymphoid and neuronal ligands. We shall also expand on our finding that lymphoid ltk is not expressed on the surface of transfected cells. We attribute this lack of surface expression to the absence of an essential subunits, leading to incorrect receptor assembly. We shall test whether transfected neuronal ltk is cytoplasmic, and whether additional lymphoid and neuronal cDNAs restore surface expression ltk. 2. To analyze the signaling pathways in which ltk functions, by creating ltk deficient mice via ES cell gene targeting. These mice may reveal whether lymphoid ltk is the receptor for a pre-B cell growth or differentiation factor. Such a factor might be a useful therapeutic agent for B cell malignancies. If our speculative hypothesis that ltk controls the survival of cells is correct, ltk-deficient mice may show progressive neurodegeneration and provide clues about human neurodegenerative disorders. 3. To use the highly expression of ltk, to identify nuclear factors that are likely to control important aspects of lymphocyte and neuronal development. This work may lead to the identification of promoter elements that allow targeted gene expression in postmitotic cerebral neurons of transgenic animals.