Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders
Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders
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DOI：
10.1111/jnc.12943
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发表时间：
2015-01-01
影响因子：
4.7
通讯作者：
Nagata, Koh-ichi
中科院分区：
文献类型：
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作者：
Mizuno, Makoto;Matsumoto, Ayumi;Nagata, Koh-ichi
使用比较基因组杂交分析自闭症谱系障碍（ASD）患者，73-Kb重复19 q13.33（nt. 49562755-49635956），包括LIN 7 B和其他5个基因。然后，我们在另一名ASD患者的LIN 7 B中发现了一种新的移码突变。由于LIN-7 B编码神经元功能所必需的支架蛋白，因此我们分析了Lin-7 B在大脑皮层发育中的作用。在子宫内电穿孔的Lin-7 B的急性敲低引起皮质生成期间神经元迁移的延迟。当Lin-7 B在一侧大脑半球的皮质神经元中被敲低时，它们的轴突在离开胼胝体后不能有效地延伸到对侧大脑半球。同时，Lin-7 B表达增强对皮层神经元迁移和轴突生长均无影响。值得注意的是，Lin-7 B的沉默并不影响神经元祖细胞和干细胞的增殖。总之，发现Lin-7 B通过调节兴奋性神经元迁移和半球间轴突生长在皮质生成中起关键作用，而需要进一步分析将Lin-7 B的功能缺陷与ASD病理生理学直接联系起来。
Using comparative genomic hybridization analysis for an autism spectrum disorder (ASD) patient, a 73-Kb duplication at 19q13.33 (nt. 49562755-49635956) including LIN7B and 5 other genes was detected. We then identified a novel frameshift mutation in LIN7B in another ASD patient. Since LIN7B encodes a scaffold protein essential for neuronal function, we analyzed the role of Lin-7B in the development of cerebral cortex. Acute knockdown of Lin-7B with in utero electroporation caused a delay in neuronal migration during corticogenesis. When Lin-7B was knocked down in cortical neurons in one hemisphere, their axons failed to extend efficiently into the contralateral hemisphere after leaving the corpus callosum. Meanwhile, enhanced expression of Lin-7B had no effects on both cortical neuron migration and axon growth. Notably, silencing of Lin-7B did not affect the proliferation of neuronal progenitors and stem cells. Taken together, Lin-7B was found to play a pivotal role in corticogenesis through the regulation of excitatory neuron migration and interhemispheric axon growth, while further analyses are required to directly link functional defects of Lin-7B to ASD pathophysiology.