The neural adhesion molecule TAG-1 modulates responses of sensory axons to diffusible guidance signals
The neural adhesion molecule TAG-1 modulates responses of sensory axons to diffusible guidance signals
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DOI：
10.1242/dev.009019
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发表时间：
2008-07-15
期刊：
影响因子：
4.6
通讯作者：
Furley, Andrew J. W.
中科院分区：
文献类型：
--
作者：
Law, Chris O.;Kirby, Rebecca J.;Furley, Andrew J. W.
初级感觉神经元的轴突投射到胚胎哺乳动物脊髓时，根据神经元亚类，它们在将侧支输送到特定的层之前分叉并向吻尾方向延伸。这种神经支配的特异性被认为是对腹侧脊髓中表达的化学排斥剂的不同敏感性和背角中Ig样神经细胞粘附分子的功能的结果。这些机制之间的关系尚未得到解决。聚焦于TrkA+ NGF依赖性轴突的寻路，我们首次证明了它们的轴突过早地投射到L1和TAG-1基因敲除小鼠的背角中。我们发现，缺乏TAG-1的轴突，类似于缺乏L1的轴突，对野生型腹侧脊髓（VSC）衍生的化学排斥剂不敏感，这表明轴突中需要粘附分子功能，并且这种响应的丧失部分地由对Sema 3A的响应丧失来解释。我们目前的证据表明，TAG-1影响敏感性Sema 3A结合L1和调节L1/神经纤毛蛋白1 Sema 3A受体复合物的内吞作用。然而，TAG-1似乎通过L1非依赖性机制影响对其他VSC衍生的化学排斥剂的敏感性。我们认为，这种依赖化学排斥剂的敏感性的粘附分子的组合的功能是重要的，以确保轴突项目通过特定的途径之前，延伸到他们的最终目标。
When the axons of primary sensory neurons project into the embryonic mammalian spinal cord, they bifurcate and extend rostrocaudally before sending collaterals to specific laminae according to neuronal subclass. The specificity of this innervation has been suggested to be the result both of differential sensitivity to chemorepellants expressed in the ventral spinal cord and of the function of Ig-like neural cell adhesion molecules in the dorsal horn. The relationship between these mechanisms has not been addressed. Focussing on the pathfinding of TrkA+ NGF-dependent axons, we demonstrate for the first time that their axons project prematurely into the dorsal horn of both L1 and TAG-1 knockout mice. We show that axons lacking TAG-1, similar to those lacking L1, are insensitive to wild-type ventral spinal cord (VSC)-derived chemorepellants, indicating that adhesion molecule function is required in the axons, and that this loss of response is explained in part by loss of response to Sema3A. We present evidence that TAG-1 affects sensitivity to Sema3A by binding to L1 and modulating the endocytosis of the L1/neuropilin 1 Sema3A receptor complex. However, TAG-1 appears to affect sensitivity to other VSC-derived chemorepellants via an L1-independent mechanism. We suggest that this dependence of chemorepellant sensitivity on the functions of combinations of adhesion molecules is important to ensure that axons project via specific pathways before extending to their final targets.