Doublecortin facilitates the elongation of the somatic Golgi apparatus into proximal dendrites.

Mutations in the doublecortin (DCX) gene, which encodes a microtubule (MT)-binding protein, cause human cortical malformations, including lissencephaly and subcortical band heterotopia. A deficiency in DCX and DCX-like kinase 1 (DCLK1), a functionally redundant and structurally similar cognate of DCX, decreases neurite length and increases the number of primary neurites directly arising from the soma. The underlying mechanism is not completely understood. In this study, the elongation of the somatic Golgi apparatus into proximal dendrites, which have been implicated in dendrite patterning, was significantly decreased in the absence of DCX/DCLK1. Phosphorylation of DCX at S47 or S327 was involved in this process. DCX deficiency shifted the distribution of CLASP2 proteins to the soma from the dendrites. In addition to CLASP2, dynein and its cofactor JIP3 were abnormally distributed in DCX-deficient neurons. The association between JIP3 and dynein was significantly increased in the absence of DCX. Down-regulation of CLASP2 or JIP3 expression with specific shRNAs rescued the Golgi phenotype observed in DCX-deficient neurons. We conclude that DCX regulates the elongation of the Golgi apparatus into proximal dendrites through MT-associated proteins and motors.

编码微管（MT）结合蛋白的双皮质素（DCX）基因突变会导致人类皮质畸形，包括无脑回畸形和皮质下带状异位。DCX以及与DCX功能冗余且结构相似的同源蛋白DCX样激酶1（DCLK1）的缺失会减少神经突长度，并增加直接从胞体发出的初级神经突数量。其潜在机制尚未完全清楚。在本研究中，在缺乏DCX/DCLK1的情况下，参与树突模式形成的胞体高尔基体向近端树突的延伸显著减少。DCX在S47或S327位点的磷酸化参与了这一过程。DCX缺失使CLASP2蛋白从树突向胞体的分布发生改变。除CLASP2外，动力蛋白及其辅因子JIP3在DCX缺失的神经元中分布异常。在缺乏DCX的情况下，JIP3和动力蛋白之间的关联显著增强。用特异性shRNAs下调CLASP2或JIP3的表达可挽救在DCX缺失神经元中观察到的高尔基体表型。我们得出结论：DCX通过微管相关蛋白和分子马达调节高尔基体向近端树突的延伸。