Kif14 mutation causes severe brain malformation and hypomyelination.
Kif14 mutation causes severe brain malformation and hypomyelination.
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DOI：
10.1371/journal.pone.0053490
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sakisaka T
中科院分区：
文献类型：
--
作者：
Fujikura K;Setsu T;Tanigaki K;Abe T;Kiyonari H;Terashima T;Sakisaka T
我们描述了一种新的自发小鼠突变体，laggard（滞后），其特征是平头，运动障碍和生长迟缓。该突变作为常染色体隐性性状遗传，lag/lag小鼠患有小脑性共济失调并在断奶前死亡。Lag / Lag小鼠表现出大脑体积的急剧缩小和视神经的细长。通过定位克隆，我们在Kif14中发现了一个剪接位点突变。与野生型Kif14-cDNA的转基因互补可减轻lag/lag小鼠的共济失调表型。为了进一步证实致病基因是Kif14，我们产生了Kif14敲除小鼠，发现Kif14敲除小鼠的所有表型都与lag/lag小鼠相似。lag/lag小鼠的主要形态学异常是中枢神经系统严重的髓鞘退化。lag/lag小鼠表达一系列髓磷脂相关基因的水平显著降低。小脑和大脑皮层细胞结构的破坏似乎是由细胞凋亡死亡引起的。因此，我们得出结论，Kif14对于髓鞘、小脑和大脑皮质等后期发育结构的产生和成熟至关重要。到目前为止，还没有报道过Kif14缺陷小鼠或Kif14突变，我们首次确定了Kif14在体内的生物学功能。哺乳动物模型的发现，为研究人员增加更多关于脑畸形病因和病理的知识开辟了视野。
We describe a novel spontaneous mouse mutant, laggard (lag), characterized by a flat head, motor impairment and growth retardation. The mutation is inherited as an autosomal recessive trait, and lag/lag mice suffer from cerebellar ataxia and die before weaning. lag/lag mice exhibit a dramatic reduction in brain size and slender optic nerves. By positional cloning, we identify a splice site mutation in Kif14. Transgenic complementation with wild-type Kif14-cDNA alleviates ataxic phenotype in lag/lag mice. To further confirm that the causative gene is Kif14, we generate Kif14 knockout mice and find that all of the phenotypes of Kif14 knockout mice are similar to those of lag/lag mice. The main morphological abnormality of lag/lag mouse is severe hypomyelination in central nervous system. The lag/lag mice express an array of myelin-related genes at significantly reduced levels. The disrupted cytoarchitecture of the cerebellar and cerebral cortices appears to result from apoptotic cell death. Thus, we conclude that Kif14 is essential for the generation and maturation of late-developing structures such as the myelin sheath, cerebellar and cerebral cortices. So far, no Kif14-deficient mice or mutation in Kif14 has ever been reported and we firstly define the biological function of Kif14 in vivo. The discovery of mammalian models, laggard, has opened up horizons for researchers to add more knowledge regarding the etiology and pathology of brain malformation.
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影响因子：
64.8
作者：
Eggenschwiler, JT;Espinoza, E;Anderson, KV
通讯作者：
Anderson, KV
DOI：
10.1083/jcb.200511061
发表时间：
2006-01-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gruneberg U;Neef R;Li X;Chan EH;Chalamalasetty RB;Nigg EA;Barr FA
通讯作者：
Barr FA
影响因子：
2.9
作者：
HERRUP, K;MULLEN, RJ
通讯作者：
MULLEN, RJ
影响因子：
4
作者：
Ponting, C;Jackson, AP
通讯作者：
Jackson, AP
影响因子：
11.2
作者：
Harrington, Emily P.;Zhao, Chao;Fancy, Stephen P. J.;Kaing, Sovann;Franklin, Robin J. M.;Rowitch, David H.
通讯作者：
Rowitch, David H.