Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice.
Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice.
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DOI：
10.1007/s00429-016-1282-1
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发表时间：
2017-04
影响因子：
3.1
通讯作者：
Velayos-Baeza A
中科院分区：
文献类型：
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作者：
Martinez-Garay I;Guidi LG;Holloway ZG;Bailey MA;Lyngholm D;Schneider T;Donnison T;Butt SJ;Monaco AP;Molnár Z;Velayos-Baeza A
发展性阅读障碍是一种常见的疾病，具有很强的遗传成分，但其潜在的分子机制仍然未知。已经在人类中鉴定了几个候选的阅读障碍易感基因，包括KIAA 0319、DYX 1C 1和DCDC 2。在大鼠胚胎中针对这些基因的RNA干扰实验显示神经元迁移受损，这表明放射状皮质迁移缺陷可能与阅读障碍的疾病机制有关。在这里，我们提出了Kiaa 0319敲除小鼠系的第一个表征。缺乏KIAA 0319蛋白的动物在大脑的任何分层结构中都没有显示出解剖学异常。皮质投射神经元的神经发生和径向迁移没有改变，Kiaa 0319缺陷神经元的内在电生理特性与野生型神经元没有区别。Kiaa 0319在皮质过度表达延迟径向迁移，但不影响最终的神经元位置。然而，基因敲除动物显示出细微的差异，这表明焦虑相关行为和感觉运动门控可能发生变化。我们的研究结果并没有揭示小鼠模型中的迁移障碍，增加了Dcdc 2和Dyx 1c 1的证据，与大鼠子宫内敲除模型不同，诵读困难易感性候选小鼠同源基因在神经元迁移中不起明显作用。然而，KIAA 0319蛋白表达似乎仅限于大脑，不仅在早期发育阶段，而且在成年小鼠中，表明该蛋白在脑功能中的作用。本文报道的组成型和条件性基因敲除株系将为Kiaa 0319的进一步功能分析提供有用的工具。本文的在线版本（doi：10.1007/s 00429 -016-1282-1）包含补充材料，可供授权用户使用。
Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319. The online version of this article (doi:10.1007/s00429-016-1282-1) contains supplementary material, which is available to authorized users.