Institute of Medical Biology, 8A Biomedical Grove, #05-37 Immunos, Singapore.
Stem Cells. 2014 Jun;32(6):1636-48. doi: 10.1002/stem.1645.
Neural stem cells (NSCs) and neural progenitors (NPs) in the mammalian neocortex give rise to the main cell types of the nervous system. The biological behavior of these NSCs and NPs is regulated by extracellular niche derived autocrine-paracrine signaling factors on a developmental timeline. Our previous reports [Plos One 2010;5:e15341; J Neurochem 2011;117:565-578] have shown that chondroitin sulfate proteoglycan and ApolipoproteinE are autocrine-paracrine survival factors for NSCs. NogoA, a myelin related protein, is expressed in the cortical ventricular zones where NSCs reside. However, the functional role of Nogo signaling proteins in NSC behavior is not completely understood. In this study, we show that NogoA receptors, NogoR1 and PirB, are expressed in the ventricular zone where NSCs reside between E10.5 and 14.5 but not at E15.5. Nogo ligands stimulate NSC survival and proliferation in a dosage-dependent manner in vitro. NogoR1 and PirB are low and high affinity Nogo receptors, respectively and are responsible for the effects of Nogo ligands on NSC behavior. Inhibition of autocrine-paracrine Nogo signaling blocks NSC survival and proliferation. In NSCs, NogoR1 functions through Rho whereas PirB uses Shp1/2 signaling pathways to control NSC behavior. Taken together, this work suggests that Nogo signaling is an important pathway for survival of NSCs.
神经干细胞（NSCs）和神经祖细胞（NPs）在哺乳动物新皮质中产生神经系统的主要细胞类型。这些 NSCs 和 NPs 的生物学行为受发育时间线上源自细胞外小生境的自分泌-旁分泌信号因子调节。我们之前的报告[Plos One 2010;5:e15341; J Neurochem 2011;117:565-578]表明，软骨素硫酸盐蛋白聚糖和载脂蛋白 E 是 NSCs 的自分泌-旁分泌存活因子。NogoA 是一种与髓鞘相关的蛋白质，在 NSCs 所在的皮质脑室区表达。然而，Nogo 信号蛋白在 NSC 行为中的功能作用尚不完全清楚。在这项研究中，我们表明 NogoA 受体 NogoR1 和 PirB 于 E10.5 至 14.5 期间在 NSCs 所在的脑室区表达，但在 E15.5 时不表达。Nogo 配体在体外以剂量依赖的方式刺激 NSC 存活和增殖。NogoR1 和 PirB 分别是低亲和性和高亲和性的 Nogo 受体，负责 Nogo 配体对 NSC 行为的影响。自分泌-旁分泌 Nogo 信号的抑制阻止了 NSC 的存活和增殖。在 NSCs 中，NogoR1 通过 Rho 发挥作用，而 PirB 则利用 Shp1/2 信号通路来控制 NSC 行为。总之，这项工作表明 Nogo 信号是 NSCs 存活的重要途径。
