Neurobiology Section, Biological Sciences Division, University of California at San Diego, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14663-8. doi: 10.1073/pnas.1206218109. Epub 2012 Aug 17.
Conditioning lesion of the peripheral branch of dorsal column axons is a well-known paradigm enabling the central branch to regenerate after injury to the spinal cord. However, only a small number of regenerating axons enter grafted substrates, and they do not grow beyond the lesion. We found that conditioning lesion induces, in addition to growth-stimulating genes, related to receptor tyrosine kinase (Ryk), a potent repulsive receptor for Wnts. Wnts are expressed around the site of spinal cord injury, and we found that grafted bone marrow stromal cells secreting the Wnt inhibitors secreted frizzled-related protein 2 or Wnt inhibitory factor 1 enhanced regeneration of the central branch after peripheral conditioning lesion. Furthermore, we found that Wnt4-expressing grafts caused dramatic long-range retraction of the injured central branch of conditioned dorsal root ganglion neurons. Macrophages accumulate along the path of receding axons but not around Wnt4-expressing cells, suggesting that the retraction of dorsal column axons is not a secondary effect of increased macrophages attracted by Wnt4. Therefore, Wnt-Ryk signaling is an inhibitory force co-induced with growth-stimulating factors after conditioning lesion. Overcoming Wnt inhibition may further enhance therapies being designed on the basis of the conditioning-lesion paradigm.
外周背柱轴突分支的条件性损伤是一种众所周知的范例，能使脊髓损伤后的中枢分支再生。然而，只有少数再生轴突进入移植物基质，而且它们不会超过损伤部位生长。我们发现，条件性损伤不仅会诱导与生长刺激基因相关的受体酪氨酸激酶（Ryk），还会诱导与 Wnt 相关的一种强烈排斥性受体。Wnt 在脊髓损伤部位周围表达，我们发现，分泌 Wnt 抑制剂卷曲相关蛋白 2 或 Wnt 抑制因子 1 的骨髓基质细胞移植物增强了外周条件性损伤后中枢分支的再生。此外，我们发现表达 Wnt4 的移植物导致条件化背根神经节神经元损伤的中枢分支发生明显的远距离回缩。巨噬细胞沿退缩轴突的路径聚集，但不聚集在表达 Wnt4 的细胞周围，这表明背柱轴突的回缩不是 Wnt4 吸引的巨噬细胞增加的继发效应。因此，Wnt-Ryk 信号是条件性损伤后与生长刺激因子共同诱导的抑制力。克服 Wnt 抑制可能会进一步增强基于条件性损伤范例设计的治疗方法。
