Institut für Molekulare Zellbiologie, University of Münster, Münster, Germany.
Cells-in-Motion Cluster of Excellence, University of Münster, Münster, Germany.
PLoS One. 2019 Jul 18;14(7):e0219362. doi: 10.1371/journal.pone.0219362. eCollection 2019.
One of the earliest steps during the development of the nervous system is the establishment of neuronal polarity and the formation of an axon. The intrinsic mechanisms that promote axon formation have been extensively analyzed. However, much less is known about the extrinsic signals that initiate axon formation. One of the candidates for these signals is Insulin-like growth factor 1 (Igf1) that acts through the Igf1 (Igf1R) and insulin receptors (InsR). Since Igf1R and InsR may act redundantly we analyzed conditional cortex-specific knockout mice that are deficient for both Igf1r and Insr to determine if they regulate the development of the cortex and the formation of axons in vivo. Our results show that Igf1R/InsR function is required for the normal development of the embryonic hippocampus and cingulate cortex while the lateral cortex does not show apparent defects in the Igf1r;Insr knockout. In the cingulate cortex, the number of intermediate progenitors and deep layer neurons is reduced and the corpus callosum is absent at E17. However, cortical organization and axon formation are not impaired in knockout embryos. In culture, cortical and hippocampal neurons from Igf1r;Insr knockout embryos extend an axon but the length of this axon is severely reduced. Our results indicate that Igf1R/InsR function is required for brain development in a region-specific manner and promotes axon growth but is not essential for neuronal polarization and migration in the developing brain.
神经系统发育过程中的早期步骤之一是神经元极性的建立和轴突的形成。促进轴突形成的内在机制已被广泛分析。然而，对于启动轴突形成的外在信号知之甚少。这些信号的候选者之一是胰岛素样生长因子 1（Igf1），它通过 Igf1（Igf1R）和胰岛素受体（InsR）起作用。由于 Igf1R 和 InsR 可能具有冗余作用，我们分析了条件性皮质特异性敲除小鼠，这些小鼠缺乏 Igf1r 和 Insr，以确定它们是否调节体内皮质的发育和轴突的形成。我们的结果表明，Igf1R/InsR 功能对于胚胎海马体和扣带皮质的正常发育是必需的，而外侧皮质在 Igf1r;Insr 敲除小鼠中没有明显缺陷。在扣带皮质中，中间祖细胞和深层神经元的数量减少，E17 时胼胝体缺失。然而，在敲除胚胎中皮质组织和轴突形成没有受损。在培养中，来自 Igf1r;Insr 敲除胚胎的皮质和海马神经元会延伸轴突，但该轴突的长度严重缩短。我们的结果表明，Igf1R/InsR 功能以区域特异性方式促进脑发育和轴突生长，但对于发育中大脑中的神经元极化和迁移不是必需的。
