The Hormonal Control of Fetal Growth

描述(申请人提供)：胰岛素样生长因子-L(IGF-I)是正常大脑发育所必需的。它已被证明对神经干细胞(NSC)和每个主要的神经细胞谱系(神经元、少突胶质细胞和星形胶质细胞)发挥作用。我们已经证明，IGF-I在神经发生早期通过刺激前体细胞增殖而增加神经元数量，后来通过抑制神经元凋亡而增加神经元数量。IGF-I还能刺激神经细胞的生长和突触的形成。此外，我们和其他人提供了令人信服的证据，表明IGF-I刺激少突胶质细胞发育和髓鞘形成，其他证据表明IGF-I指示NSC致力于少突胶质细胞谱系。这些数据提出了一个问题，即IGF-I如何才能引起如此广泛的反应。这一建议是基于这样一个概念，即在体内IGF-I的反应取决于上下文。我们将检验以下工作假说：1)IGF-I刺激神经干细胞和每个神经谱系命运决定的前体细胞的增殖；2)IGF-I不决定谱系命运；3)IGF-I是终生神经前体细胞(NP)增殖的主要刺激因子，对神经发生和继发性损伤起显著作用。我们的研究将集中在发育中的齿状回(DG)，因为它保留了NSC和在一生中产生新神经细胞的能力。我们将针对3个具体目标：1.为了了解IGF-I作用的背景，我们将使用激光捕获显微解剖和RT-PCR来定义在正常小鼠DG发育过程中和新生儿缺氧/缺血损伤后表达IGFS、1型受体(IGF1R)和IGF结合蛋白(IGFBP)的精确细胞；II.使用IGF-I表达改变的突变小鼠(IGF-I空白小鼠和从神经发育早期过表达IGF-I的小鼠)或ACTION(在NP中IGF1R表达减弱的小鼠)，我们将研究IGF-I对DG NSC增殖、NSC命运和发育过程中神经发生的影响；以及III.确定新生儿缺血/缺氧对正常和IGF-I和IGF1R突变小鼠DG神经发生的影响。

DESCRIPTION (provided by applicant): Insulin-like growth factor-l (IGF-I) is essential to normal brain growth. It has been shown to exert actions on neural stem cells (NSC) and each major neural cell lineage (neurons, oligodendrocytes, and astrocytes). We have demonstrated that IGF-I increases neuron number by stimulating progenitor proliferation early in neurogenesis and later by inhibiting neuron apoptosis. IGF-I also stimulates neuritic outgrowth and synaptogenesis. Furthermore we, and others, have provided compelling evidence that IGF-I stimulates oligodendrocyte development and myelination, and other evidence suggests that IGF-I instructs NSC to commit to the oligodendrocyte lineage. This data raises the question of how IGF-I can elicit such a wide variety of responses. This proposal is based on the concept that in vivo IGF-I responses are dependent upon context. We will test the following working hypotheses: 1) IGF-I stimulates the proliferation of NSC and fate-committed precursors of each neural lineage; 2) IGF-I does not determine lineage fate; and 3) IGF-I is a major stimulator of neuron progenitor (NP) proliferation throughout life, exerting marked effects on neurogenesis and following injury. Our studies will focus on the developing dentate gyrus (DG) because it retains NSC and the capacity to generate new neural cells throughout life. We will address 3 specific aims: I. To understand the context of IGF-I actions, we will use laser capture microdissection and rtPCR to define the precise cells that express the IGFs, the type 1 receptor (IGF1R) and IGF binding proteins (IGFBP) during normal mouse DG development and following neonatal hypoxic/ischemic injury; II. Using mutant mice with altered IGF-I expression (IGF-I nulls and mice that overexpress IGF-I from early in neural development) or action (mice with ablated IGF1R expression in NP), we will investigate IGF-I effects on DG NSC proliferation, NSC fate, and neurogenesis during development; and III. Determine the consequences of neonatal ischemia/hypoxia on DG neurogenesis in normal and IGF-I and IGF1R mutant mice.