Cellular Form of Prion Protein Inhibits Reelin-Mediated Shedding of Caspr from the Neuronal Cell Surface to Potentiate Caspr-Mediated Inhibition of Neurite Outgrowth
Cellular Form of Prion Protein Inhibits Reelin-Mediated Shedding of Caspr from the Neuronal Cell Surface to Potentiate Caspr-Mediated Inhibition of Neurite Outgrowth
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DOI：
10.1523/jneurosci.5657-09.2010
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发表时间：
2010-07-07
影响因子：
5.3
通讯作者：
Schachner, Melitta
中科院分区：
文献类型：
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作者：
Devanathan, Vasudharani;Jakovcevski, Igor;Schachner, Melitta
轴突和树突在中枢神经系统的延伸受到促进生长和抑制生长的信号的严格调控，以确保突触连接的准确性。我们发现了接触蛋白相关蛋白(CASPR)的一个新作用，它是一种抑制信号，可以减少中枢神经系统神经元突起的生长。我们发现，CASPR在细胞表面的蛋白分解受PrP的细胞形式的调节，PrP直接与CASPR结合。PRP抑制Reelin介导的CASPR从细胞表面脱落，从而增加CASPR的表面水平，增强CASPR对轴突生长的抑制作用。PRP缺乏导致细胞表面CASPR水平降低，促进体外轴突生长，并在脊髓损伤后更有效地在体内再生轴突。因此，我们揭示了CASPR和PrP在抑制中枢神经系统神经元突起生长中的作用，这一作用被Reelin的蛋白分解活性所抵消。
Extension of axonal and dendritic processes in the CNS is tightly regulated by outgrowth-promoting and -inhibitory cues to assure precision of synaptic connections. We identify a novel role for contactin-associated protein (Caspr) as an inhibitory cue that reduces neurite outgrowth from CNS neurons. We show that proteolysis of Caspr at the cell surface is regulated by the cellular form of prion protein (PrP), which directly binds to Caspr. PrP inhibits Reelin-mediated shedding of Caspr from the cell surface, thereby increasing surface levels of Caspr and potentiating the inhibitory effect of Caspr on neurite outgrowth. PrP deficiency results in reduced levels of Caspr at the cell surface, enhanced neurite outgrowth in vitro, and more efficient regeneration of axons in vivo following spinal cord injury. Thus, we reveal a previously unrecognized role for Caspr and PrP in inhibitory modulation of neurite outgrowth in CNS neurons, which is counterbalanced by the proteolytic activity of Reelin.