Division of Molecular and Cellular Neuroscience, Institute of Cell Biology and Neuroscience (IBCN)-CONICET-UBA, School of Medicine, University of Buenos Aires (UBA), Buenos Aires CP 1121, Argentina.
Division of Molecular and Cellular Neuroscience, Institute of Cell Biology and Neuroscience (IBCN)-CONICET-UBA, School of Medicine, University of Buenos Aires (UBA), Buenos Aires CP 1121, Argentina.
Stem Cell Reports. 2018 Mar 13;10(3):1000-1015. doi: 10.1016/j.stemcr.2018.01.019. Epub 2018 Mar 1.
The balance between factors leading to proliferation and differentiation of cortical neural precursors (CNPs) determines the correct cortical development. In this work, we show that GDNF and its receptor GFRα1 are expressed in the neocortex during the period of cortical neurogenesis. We show that the GDNF/GFRα1 complex inhibits the self-renewal capacity of mouse CNP cells induced by fibroblast growth factor 2 (FGF2), promoting neuronal differentiation. While GDNF leads to decreased proliferation of cultured cortical precursor cells, ablation of GFRα1 in glutamatergic cortical precursors enhances its proliferation. We show that GDNF treatment of CNPs promoted morphological differentiation even in the presence of the self-renewal-promoting factor, FGF2. Analysis of GFRα1-deficient mice shows an increase in the number of cycling cells during cortical development and a reduction in dendrite development of cortical GFRα1-expressing neurons. Together, these results indicate that GDNF/GFRα1 signaling plays an essential role in regulating the proliferative condition and the differentiation of cortical progenitors.
皮质神经前体细胞（CNP）增殖和分化的平衡决定了皮质的正确发育。在这项工作中，我们发现 GDNF 及其受体 GFRα1 在皮质神经发生期间表达于新皮质。我们发现 GDNF/GFRα1 复合物抑制成纤维细胞生长因子 2（FGF2）诱导的小鼠 CNP 细胞的自我更新能力，促进神经元分化。虽然 GDNF 导致培养的皮质前体细胞增殖减少，但在谷氨酸能皮质前体细胞中敲除 GFRα1 会增强其增殖。我们发现，即使存在促进自我更新的因子 FGF2，GDNF 处理 CNP 也能促进形态分化。对 GFRα1 缺陷小鼠的分析表明，皮质发育过程中细胞周期的数量增加，表达 GFRα1 的皮质神经元的树突发育减少。综上所述，这些结果表明 GDNF/GFRα1 信号在调节皮质祖细胞的增殖状态和分化中起着至关重要的作用。
