Ye Ping, Popken Greg J, Kemper April, McCarthy Ken, Popko Brian, D'Ercole A Joseph
Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
J Neurosci Res. 2004 Nov 15;78(4):472-84. doi: 10.1002/jnr.20288.
Insulin-like growth factor-I (IGF-I) is widely expressed in the central nervous system (CNS). Whereas during normal development IGF-I is expressed predominantly by neurons and to a much lesser degree by glial cells, its expression in astrocytes, and often in microglia, is increased during and/or after variety of CNS injuries. Recently we have generated a new line of IGF-I Tg mice, called IGF-I(Ast/Tet-Off) Tg mice, in which IGF-I transgene is expressed specifically in astrocytes and is tightly controlled by the tetracycline analog doxycycline. In this study we examined whether IGF-I derived from astrocytes is capable of promoting neural cell growth during development. When the IGF-I transgene is allowed to be expressed, IGF-I(Ast/Tet-Off) Tg mice exhibit markedly increases in 1) brain weight; 2) brain DNA and protein abundance; and 3) number of neurons, oligodendrocytes, and astrocytes, as well as myelination, findings similar to those observed in our other lines of Tg mice that express IGF-I transgene predominantly in neurons. Unlike Tg mice with neuron-specific IGF-I expression, which manifest marked increases in the concentrations of oligodendrocyte/myelin-specific proteins, however, IGF-I(Ast/Tet-Off) Tg mice exhibit an increase in the concentration of glial fibrillary acidic protein, an astrocyte-specific protein. Furthermore, when transgene expression is blunted, brain overgrowth in IGF-I(Ast/Tet-Off) Tg mice ceases. Our data indicate that astrocyte-derived IGF-I is capable of promoting neural cells growth in vivo. Our data also suggest that IGF-I's actions in CNS depend in part on the location of its expression and cellular microenvironment and that continuous presence of IGF-I expression is necessary for brain overgrowth.
胰岛素样生长因子-I（IGF-I）在中枢神经系统（CNS）中广泛表达。在正常发育过程中，IGF-I主要由神经元表达，而胶质细胞表达程度较低，但在各种中枢神经系统损伤期间和/或之后，其在星形胶质细胞以及通常在小胶质细胞中的表达会增加。最近我们培育出了一种新的IGF-I转基因小鼠品系，称为IGF-I（Ast/Tet-Off）转基因小鼠，其中IGF-I转基因在星形胶质细胞中特异性表达，并受到四环素类似物强力霉素的严格调控。在本研究中，我们检测了星形胶质细胞来源的IGF-I在发育过程中是否能够促进神经细胞生长。当允许IGF-I转基因表达时，IGF-I（Ast/Tet-Off）转基因小鼠在以下方面表现出显著增加：1）脑重量；2）脑DNA和蛋白质丰度；3）神经元、少突胶质细胞和星形胶质细胞的数量以及髓鞘形成，这些发现与我们其他主要在神经元中表达IGF-I转基因的转基因小鼠品系中观察到的结果相似。然而，与神经元特异性表达IGF-I的转基因小鼠不同，后者表现出少突胶质细胞/髓鞘特异性蛋白浓度显著增加，而IGF-I（Ast/Tet-Off）转基因小鼠则表现出星形胶质细胞特异性蛋白胶质纤维酸性蛋白浓度增加。此外，当转基因表达受到抑制时，IGF-I（Ast/Tet-Off）转基因小鼠的脑过度生长停止。我们的数据表明，星形胶质细胞来源的IGF-I能够在体内促进神经细胞生长。我们的数据还表明，IGF-I在中枢神经系统中的作用部分取决于其表达位置和细胞微环境，并且IGF-I表达的持续存在对于脑过度生长是必要的。
