Doublecortin (DCX) mediates endocytosis of neurofascin independently of microtubule binding.
Doublecortin (DCX) mediates endocytosis of neurofascin independently of microtubule binding.
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DOI：
10.1523/jneurosci.5318-11.2012
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发表时间：
2012-05-30
期刊：
影响因子：
--
通讯作者：
Winckler B
中科院分区：
文献类型：
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作者：
Yap CC;Vakulenko M;Kruczek K;Motamedi B;Digilio L;Liu JS;Winckler B
双皮质素（DCX）是人类无脑回畸形的两个主要遗传位点之一，无脑回畸形是一种神经元迁移和轴突生长缺陷的神经发育障碍。DCX是一种微管结合蛋白，许多工作都集中在其微管相关的功能。DCX有其他报道的结合伙伴，包括细胞粘附分子神经成束蛋白，但DCX-神经成束蛋白相互作用的功能意义尚不清楚。神经成束蛋白强烈地定位于成熟神经元中的轴突起始段，在那里它在组装和维持其他轴突起始段组分中起作用。在发育过程中，神经成束蛋白可能在轴突导向和GABA能突触发生中发挥额外的作用。我们在这里表明，DCX可以调节神经成束蛋白在发育中的培养大鼠神经元的表面分布，从而轴突起始段之间的相对程度的积累，和索马和树突。机制上，DCX通过增加来自索马和树突的神经成束蛋白的内吞作用起作用。令人惊讶的是，DCX增加神经成束蛋白内吞作用显然独立于其微管结合活性。我们还表明，患者等位基因DCXG 253 D仍然结合微管，但缺乏促进NF内吞。我们建议，DCX作为一个内吞适配器神经成束蛋白微调其表面分布在神经元发育过程中。
Doublecortin (DCX) is one of two major genetic loci underlying human lissencephaly, a neurodevelopmental disorder with defects in neuronal migration and axon outgrowth. DCX is a microtubule-binding protein, and much work has focused on its microtubule-associated functions. DCX has other reported binding partners, including the cell adhesion molecule neurofascin, but the functional significance of the DCX-neurofascin interaction is not understood. Neurofascin localizes strongly to the axon initial segment in mature neurons where it plays a role in assembling and maintaining other axon initial segment components. During development, neurofascin likely plays additional roles in axon guidance and in GABAergic synaptogenesis. We show here that DCX can modulate the surface distribution of neurofascin in developing cultured rat neurons, and thereby the relative extent of accumulation between the axon initial segment, and soma and dendrites. Mechanistically, DCX acts via increasing endocytosis of neurofascin from soma and dendrites. Surprisingly, DCX increases neurofascin endocytosis apparently independently of its microtubule-binding activity. We additionally show that the patient allele DCXG253D still binds microtubules, but is deficient in promoting NF endocytosis. We propose that DCX acts as an endocytic adaptor for neurofascin to fine-tune its surface distribution during neuronal development.