Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A
Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A
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DOI：
10.1093/emboj/cdf645
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发表时间：
2002-12-02
期刊：
影响因子：
11.4
通讯作者：
Rougon, G
中科院分区：
文献类型：
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作者：
Castellani, V;De Angelis, E;Rougon, G
由于几个大脑结构和纤维束的异常发育，L1基因的突变会导致一系列人类神经疾病。在其结合伙伴中，L1免疫球蛋白超家族黏附分子(Ig CAM)与神经粘连蛋白-1(NP-1)结合形成信号素3A(Sema3A)受体，而可溶性L1将Sema3A诱导的轴突排斥转化为吸引。使用含有错义病理突变的L1构建体，我们在这里表明，这种逆转是由L1与NP-1的特异性反式结合启动的，而不是由L1或其他Ig CAM的反式结合启动的，并导致NO/cGMP途径的激活。我们在L1Ig结构域1的限制性序列中确定了L1-NP-1结合位点，因为从该区域衍生的多肽可以逆转Sema3A的排斥效应。位于该序列中的病理性L1错义突变特异性地破坏了L1-NP-1复合体的形成和Sema3A的逆转，表明L1和Sema3A之间的串扰可能参与了人脑的发育。
Mutations in the L1 gene induce a spectrum of human neurological disorders due to abnormal development of several brain structures and fiber tracts. Among its binding partners, L1 immunoglobulin superfamily adhesion molecule (Ig CAM) associates with neuropilin-1 (NP-1) to form a semaphorin3A (Sema3A) receptor and soluble L1 converts Sema3A-induced axonal repulsion into attraction. Using L1 constructs containing missense pathological mutations, we show here that this reversion is initiated by a specific trans binding of L1 to NP-1, but not to L1 or other Ig CAMS, and leads to activation of the NO/cGMP pathway. We identified the L1-NP-1-binding site in a restricted sequence of L1 Ig domain 1, as a peptide derived from this region could reverse Sema3A repulsive effects. A pathological L1 missense mutation located in this sequence specifically disrupts both L1-NP-1 complex formation and Sema3A reversion, suggesting that the cross-talk between L1 and Sema3A might participate in human brain development.