Loss of glial fibrillary acidic protein (GFAP) impairs Schwann cell proliferation and delays nerve regeneration after damage
Loss of glial fibrillary acidic protein (GFAP) impairs Schwann cell proliferation and delays nerve regeneration after damage
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DOI：
10.1242/jcs.03168
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发表时间：
2006-10-01
影响因子：
4
通讯作者：
Previtali, Stefano C.
中科院分区：
文献类型：
--
作者：
Triolo, Daniela;Dina, Giorgia;Previtali, Stefano C.
轴突损失会导致许多周围神经病的致残和永久性缺陷，并且可能是由于雪旺细胞、轴突和细胞外基质之间的关系缺陷导致神经再生效率低下所致。这些相互作用由表面受体介导并由细胞骨架分子转导。我们研究了缺乏神经胶质纤维酸性蛋白（GFAP）的小鼠周围神经再生是否受到干扰，GFAP是一种在损伤后上调的雪旺细胞特异性细胞骨架成分。 GFAP 缺失小鼠的周围神经发育和功能正常。然而，损伤后轴突再生被延迟。突变的雪旺细胞保持了去分化的能力，但表现出增殖缺陷，这是成功神经再生的关键事件。我们还表明，GFAP 和其他雪旺细胞中间丝波形蛋白在涉及增殖和神经再生的两个不同信号通路中发生物理相互作用。 GFAP 结合整合素 α v beta 8，在损伤后不久通过与纤维蛋白相互作用启动有丝分裂信号。一致地，在压碎的 GFAP 缺失神经中，ERK 磷酸化减少。相反，波形蛋白与整合素 α 5 β 1 结合，调节再生后期的增殖和分化，并可能补偿突变小鼠中 GFAP 的缺失。 GFAP 可能有助于形成大复合物，以启动有丝分裂和分化信号传导，从而实现有效的神经再生。
Axonal loss causes disabling and permanent deficits in many peripheral neuropathies, and may result from inefficient nerve regeneration due to a defective relationship between Schwann cells, axons and the extracellular matrix. These interactions are mediated by surface receptors and transduced by cytoskeletal molecules. We investigated whether peripheral nerve regeneration is perturbed in mice that lack glial fibrillary acidic protein (GFAP), a Schwann-cell-specific cytoskeleton constituent upregulated after damage. Peripheral nerves develop and function normally in GFAP-null mice. However, axonal regeneration after damage was delayed. Mutant Schwann cells maintained the ability to dedifferentiate but showed defective proliferation, a key event for successful nerve regeneration. We also showed that GFAP and the other Schwann-cell-intermediate filament vimentin physically interact in two distinct signaling pathways involved in proliferation and nerve regeneration. GFAP binds integrin alpha v beta 8, which initiates mitotic signals soon after damage by interacting with fibrin. Consistently, ERK phosphorylation was reduced in crushed GFAP-null nerves. Vimentin instead binds integrin alpha 5 beta 1, which regulates proliferation and differentiation later in regeneration, and may compensate for the absence of GFAP in mutant mice. GFAP might contribute to form macro-complexes to initiate mitogenic and differentiating signaling for efficient nerve regeneration.