D'Ercole A J, Ye P, Calikoglu A S, Gutierrez-Ospina G
Department of Pediatrics CB# 7220, University of North Carolina, Chapel Hill 27599-7220, USA.
Mol Neurobiol. 1996 Dec;13(3):227-55. doi: 10.1007/BF02740625.
Increasing evidence strongly supports a role for insulin-like growth factor-I (IGF-I) in central nervous system (CNS) development. IGF-I, IGF-II, the type IIGF receptor (the cell surface tyrosine kinase receptor that mediates IGF signals), and some IGF binding proteins (IGFBPs; secreted proteins that modulate IGF actions) are expressed in many regions of the CNS beginning in utero. The expression pattern of IGF system proteins during brain growth suggests highly regulated and developmentally timed IGF actions on specific neural cell populations. IGF-I expression is predominantly in neurons and, in many brain regions, peaks in a fashion temporally coincident with periods in development when neuron progenitor proliferation and/or neuritic outgrowth occurs. In contrast, IGF-II expression is confined mainly to cells of mesenchymal and neural crest origin. While expression of type I IGF receptors appears ubiquitous, that of IGFBPs is characterized by regional and developmental specificity, and often occurs coordinately with peaks of IGF expression. In vitro IGF-I has been shown to stimulate the proliferation of neuron progenitors and/or the survival of neurons and oligodendrocytes, and in some cultured neurons, to stimulate function. Transgenic (Tg) mice that overexpress IGF-I in the brain exhibit postnatal brain overgrowth without anatomic abnormality (20-85% increases in weight, depending on the magnitude of expression). In contrast, Tg mice that exhibit ectopic brain expression of IGFBP-1, an inhibitor of IGF action when present in molar excess, manifest postnatal brain growth retardation, and mice with ablated IGF-I gene expression, accomplished by homologous recombination, have brains that are 60% of normal size as adults. Taken together, these in vivo studies indicate that IGF-I can influence the development of most, if not all, brain regions, and suggest that the cerebral cortex and cerebellum are especially sensitive to IGF-I actions. IGF-I's growth-promoting in vivo actions result from its capacity to increase neuron number, at least in certain populations, and from its potent stimulation of myelination. These IGF-I actions, taken together with its neuroprotective effects following CNS and peripheral nerve injury, suggest that it may be of therapeutic benefit in a wide variety of disorders affecting the nervous system.
越来越多的证据有力地支持胰岛素样生长因子-I（IGF-I）在中枢神经系统（CNS）发育中发挥作用。IGF-I、IGF-II、I型IGF受体（介导IGF信号的细胞表面酪氨酸激酶受体）以及一些IGF结合蛋白（IGFBPs；调节IGF作用的分泌蛋白）在子宫内就开始在CNS的许多区域表达。脑生长过程中IGF系统蛋白的表达模式表明，IGF对特定神经细胞群体的作用受到高度调控且具有发育时间性。IGF-I主要在神经元中表达，并且在许多脑区，其表达高峰在时间上与神经元祖细胞增殖和/或神经突生长的发育阶段一致。相比之下，IGF-II的表达主要局限于间充质和神经嵴来源的细胞。虽然I型IGF受体的表达似乎无处不在，但IGFBPs的表达具有区域和发育特异性，并且常常与IGF表达高峰协同发生。体外实验表明，IGF-I能刺激神经元祖细胞的增殖和/或神经元及少突胶质细胞的存活，并且在一些培养的神经元中能刺激其功能。在大脑中过度表达IGF-I的转基因（Tg）小鼠出生后脑过度生长且无解剖学异常（体重增加20 - 85%，具体取决于表达程度）。相反，异位表达IGFBP-1（当以摩尔过量存在时为IGF作用抑制剂）的Tg小鼠表现出出生后脑生长迟缓，而通过同源重组实现IGF-I基因表达缺失的小鼠，成年后脑大小仅为正常大小的60%。综上所述，这些体内研究表明IGF-I能影响大多数（如果不是全部）脑区的发育，并提示大脑皮层和小脑对IGF-I的作用尤为敏感。IGF-I在体内的促生长作用源于其增加神经元数量的能力（至少在某些群体中如此）以及对髓鞘形成的有力刺激。IGF-I的这些作用，连同其在CNS和周围神经损伤后的神经保护作用，表明它可能对多种影响神经系统的疾病具有治疗益处。
