Mechanism of IGF-I actions on oligodendroglial cells

描述(申请人提供)：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的发育中发挥重要作用，包括少突胶质细胞谱系细胞和髓鞘形成，以及促进损伤后少突胶质细胞谱系细胞的再生。我们假设IGF-I直接作用于少突胶质细胞系的细胞，其机制是通过与其细胞表面受体-1型IGF受体(IGF1R)的相互作用启动的，进而通过调节基因表达来启动。我们的假设得到了我们和其他研究者数据的支持，这些数据表明：1)IGF-I促进培养的少突胶质细胞系细胞的增殖和分化；2)在转基因(TG)小鼠出生后的发育过程中，IGF-I的过表达增加了少突胶质细胞系细胞的数量；3)在遭受脱髓鞘损伤的动物中，IGF-I和IGF1R基因的诱导表达与损伤的时空分布有关；4)IGF-I对多种中枢神经系统损伤的髓鞘形成具有保护作用；5)抑制IGFIR的特异性表达会导致突变小鼠脑发育迟缓和髓鞘化。此外，我们最近的研究表明，IGF-I调控少突胶质细胞系细胞中多个基因的表达和组蛋白的修饰。在这一应用中，我们提出了两个特定的目标来进一步检验我们的假设：1)为了确定IGF在体内对少突胶质细胞前体发育的作用，我们将检测新发育的在胚胎和出生后早期发育中过表达IGF-I的TG小鼠，以及在IGF1R在少突胶质细胞前体中特异性钝化表达的突变小鼠中。2)为了阐明IGF-I促进少突胶质细胞发育的基因调控的信号机制，我们将利用激光捕获显微切割和DNA阵列技术确定a)IGF-I在体内对少突胶质细胞及其前体细胞整体基因表达的调节；以及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.