Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia.
Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia.
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DOI：
10.1523/jneurosci.4516-08.2009
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发表时间：
2009-01-28
期刊：
影响因子：
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通讯作者：
Vaccarino FM
中科院分区：
文献类型：
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作者：
Fagel DM;Ganat Y;Cheng E;Silbereis J;Ohkubo Y;Ment LR;Vaccarino FM
慢性出生后缺氧导致明显的皮质神经元丢失，而在恢复过程中则相反(Exp Neurol 199，77-91)。这种可塑性背后的细胞和分子机制尚不清楚。在这里，我们表明，从出生后第3天到第10天的慢性缺氧导致皮质神经元减少30%，皮质体积减少24%。损伤后1个月，T-脑-1(Tbr1)+和Smi-32+兴奋性神经元数量完全恢复，但小白蛋白+和Calretinin+GABA能中间神经元残留缺失。相比之下，在GFAP+细胞(FGFR1CKO)中携带破碎性成纤维细胞生长因子受体-1(FGFR1)基因的低氧小鼠，表现出兴奋性皮质神经元的持续性丧失和中间神经元缺陷的恶化。标记P17的增殖前体细胞显示，在受到低氧伤害的野生型小鼠中，皮质Neun+和Tbr1+兴奋性神经元的生成增加，而FGFR1 CKO未能启动皮质神经遗传反应。与常氧小鼠相比，低氧野生型小鼠在P17时脑室下区(SVZ)的细胞增殖增加了2倍，在P48时嗅球(OB)的神经发生增加了3倍。相比之下，FGFR1CKO小鼠降低了SVZ细胞的增殖，并减少了OB中的反应性神经发生。因此，GFAP+细胞中FGFR1的激活是新生儿缺氧损伤后神经元恢复所必需的，这在一定程度上可归因于促进皮质和OB神经发生。相反，损伤后抑制性神经元不完全恢复，这可能是持续性行为缺陷的原因。
Chronic postnatal hypoxia causes an apparent loss of cortical neurons that is reversed during recovery (Exp Neurol 199, 77–91). The cellular and molecular mechanisms underlying this plasticity are not understood. Here we show that chronic hypoxia from postnatal days 3 to 10 causes a 30% decrease in cortical neurons and a 24% decrease in cortical volume. T-brain-1 (Tbr1)+ and SMI-32+ excitatory neuron numbers were completely recovered one month after the insult, but the mice showed a residual deficit in Parvalbumin+ and Calretinin+ GABAergic interneurons. In contrast, hypoxic mice carrying a disrupted Fibroblast Growth Factor Receptor-1 (Fgfr1) gene in GFAP+ cells (Fgfr1 cKO), demonstrated a persistent loss of excitatory cortical neurons and a worsening of the interneuron defect. Labeling proliferating progenitors at P17 revealed increased generation of cortical NeuN+ and Tbr1+ excitatory neurons in wild type mice subjected to hypoxic insult, whereas Fgfr1 cKO failed to mount a cortical neurogenetic response. Hypoxic wild type mice also demonstrated a two-fold increase in cell proliferation in the subventricular zone (SVZ) at P17 and a 3-fold increase in neurogenesis in the olfactory bulb (OB) at P48, as compared to normoxic mice. In contrast, Fgfr1 cKO mice had decreased SVZ cell proliferation and curtailed reactive neurogenesis in the OB. Thus, the activation of Fgfr1 in GFAP+ cells is required for neuronal recovery after neonatal hypoxic injury, which is attributable in part to enhanced cortical and OB neurogenesis. In contrast, there is incomplete recovery of inhibitory neurons after injury, which may account for persistent behavioral deficits.