Neuroanatomy & Interdisciplinary Center for Neurosiences (IZN), University of Heidelberg, Heidelberg, Germany.
Mol Cell Neurosci. 2011 Feb;46(2):483-97. doi: 10.1016/j.mcn.2010.12.001. Epub 2010 Dec 9.
The extracellular membrane-associated protein F-spondin has been implicated in cell-matrix and cell-cell adhesion and plays an important role in axonal pathfinding. We report here that F-spondin is expressed in non-neuronal cells in the embryonic chicken ciliary ganglion (CG) and robustly promotes survival of cultured CG neurons. Using deletion constructs of F-spondin we found that the amino-terminal Reelin/Spondin domain cooperates with thrombospondin type 1 repeat (TSR) 6, a functional TGFβ-activation domain. In ovo treatment with blocking antibodies raised against the Reelin/Spondin domain or the TSR-domains caused increased apoptosis of CG neurons during the phase of programmed cell death and loss of about 30% of the neurons compared to controls. The Reelin/Spondin domain receptor - APP and its downstream signalling molecule disabled-1 are expressed in CG neurons. F-spondin induced rapid phosphorylation of disabled-1. Moreover, both blocking the central APP domain and interference with disabled-1 signalling disrupted the survival promoting effect of F-spondin. Taken together, our data suggest that F-spondin can promote neuron survival by a mechanism involving the Reelin/Spondin and the TSR domains.
细胞外膜相关蛋白 F-spondin 参与细胞-基质和细胞-细胞黏附，并在轴突寻径中发挥重要作用。我们在此报告，F-spondin 在胚胎鸡睫状神经节（CG）的非神经元细胞中表达，并强烈促进培养的 CG 神经元的存活。使用 F-spondin 的缺失构建体，我们发现氨基末端 Reelin/Spondin 结构域与血栓素受体 1 重复（TSR）6 合作，这是一个功能性 TGFβ 激活结构域。在鸡胚中用针对 Reelin/Spondin 结构域或 TSR 结构域的阻断抗体处理，导致 CG 神经元在程序性细胞死亡阶段的细胞凋亡增加，与对照组相比，神经元损失约 30%。Reelin/Spondin 结构域受体 APP 和其下游信号分子 disabled-1 在 CG 神经元中表达。F-spondin 诱导 disabled-1 的快速磷酸化。此外，阻断中央 APP 结构域和干扰 disabled-1 信号均破坏了 F-spondin 的促存活作用。总之，我们的数据表明，F-spondin 可以通过涉及 Reelin/Spondin 和 TSR 结构域的机制促进神经元存活。
