Mechanism of IGF-I actions on oligodendroglial cells

描述（由申请方提供）：越来越多的证据表明，胰岛素样生长因子-I（IGF-I）在中枢神经系统神经细胞（包括少突胶质细胞谱系细胞和髓鞘形成）的发育中发挥重要作用，并促进损伤后少突胶质细胞谱系细胞的再生。我们假设IGF-I通过与其细胞表面受体1型IGF受体（IGF 1 R）相互作用而启动的机制直接作用于少突胶质细胞谱系的细胞，进而通过调节基因表达。我们的假设得到了我们和其他人的数据的支持，这些数据表明：1）IGF-I促进培养中少突胶质细胞系细胞的增殖和分化：2）在出生后发育的转基因（Tg）小鼠中IGF-I的过表达增加了少突胶质细胞系细胞的数量; 3）在经历脱髓鞘损伤的动物中，IGF-I和IGF 1 R基因的表达以与损伤时间和空间相关的方式被诱导; 4）IGF-I保护髓鞘形成免受各种CNS损伤;和5）在少突胶质细胞中特异性地钝化IGF 1 R表达导致突变小鼠的脑发育迟缓和髓鞘形成不足。此外，我们最近的研究表明，IGF-I调节少突胶质细胞系中多个基因的表达和组蛋白的修饰。在本申请中，我们提出了两个具体的目的，以进一步检验我们的假设：1）为了确定IGF对体内少突胶质细胞前体发育的作用，我们将在新开发的Tg小鼠中检查少突胶质细胞前体，这些小鼠在胚胎和出生后早期发育期间过表达IGF-I，以及在突变小鼠中，IGF 1 R表达在少突胶质细胞前体中特异性钝化。2)为了描述IGF-I信号传导机制导致促进少突胶质细胞发育的基因调节，我们将确定a）IGF-I在体内使用激光捕获显微切割和DNA阵列对少突胶质细胞及其前体中的整体基因表达的调节;和B）IGF-I对染色质重塑的作用。

DESCRIPTION (provided by applicant): Increasing evidence indicates that insulin-like growth factor-I (IGF-I) plays an important role in the development of neural cells in the central nervous system, including oligodendrocyte lineage cells and myelination, as well as promoting regeneration of oligodendrocyte lineage cells following injury. We hypothesize that IGF-I acts directly on the cells of oligodendrocyte lineage by mechanisms that are initiated by interaction with its cell surface receptor, the type 1 IGF receptor (IGF1R), and in turn by regulation of gene expression. Our hypothesis is supported by our data and those of others showing that: 1) IGF-I promotes proliferation and differentiation of oligodendrocyte lineage cells in culture; 2) overexpression of IGF-I in transgenic (Tg) mice during postnatal development increases the number of oligodendrocyte lineage cells; 3) in animals subjected to demyelinating insults, the expression of IGF-I and IGF1R genes is induced in a fashion temporally and spatially related to the injury; 4) IGF-I protects myelination from a variety of CNS injury; and 5) blunting IGFIR expression specifically in oligodendrocytes results in brain retardation and hypomyelination in the mutant mice. Furthermore, our recent studies show that IGF-I regulates multiple gene expression and modification of histone proteins in cells of oligodendrocyte line. In this application, we propose two specific aims to further examine our hypotheses: 1) To determine IGF actions on the development of oligodendrocyte precursors in vivo, we will examine oligodendrocyte precursors in newly developed Tg mice that overexpress IGF-I during embryonic and early postnatal development, and in mutant mice in which IGF1R expression is specifically blunted in oligodendrocyte precursors. 2) To delineate IGF-I signaling mechanisms leading to the gene regulation that promotes oligodendrocyte development, we will determine a) IGF-I in vivo regulation of global gene expression in oligodendrocytes and their precursors using laser captured microdissection and DNA array; and b) IGF-I actions on chromatin remodeling.