Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia.
Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia.
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DOI：
10.1038/srep31126
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发表时间：
2016-09-27
影响因子：
4.6
通讯作者：
Ding YQ
中科院分区：
文献类型：
--
作者：
Lang B;Zhang L;Jiang G;Hu L;Lan W;Zhao L;Hunter I;Pruski M;Song NN;Huang Y;Zhang L;St Clair D;McCaig CD;Ding YQ
精神分裂症是一种使人衰弱的家族性神经精神障碍，影响全世界1%的人。虽然精神分裂症的遗传率接近80%，但只有一小部分的整体遗传风险已被考虑，迄今为止，只有有限数量的遗传位点已被明确牵连。我们最近通过遗传学和体外功能研究，发现了一种新的丝氨酸/苏氨酸激酶基因，unc-51样激酶4（ULK 4），作为一种罕见的危险因素，主要精神疾病，包括精神分裂症。现在使用子宫内基因转移的方法，我们已经发现Ulk 4在皮质生成中起着关键的调节作用。Ulk 4的敲除导致生发区的细胞增殖显著降低，并导致径向迁移和神经突分支的严重缺陷。这些异常可以通过Ulk 4基因补充成功逆转。Ulk 4还调节α-微管蛋白的乙酰化，这是微管的重要翻译后修饰。我们的结论是，Ulk 4在正常的大脑发育中起着至关重要的作用，当有缺陷时，神经发育障碍如精神分裂症的风险会增加。
Schizophrenia is a debilitating familial neuropsychiatric disorder which affects 1% of people worldwide. Although the heritability for schizophrenia approaches 80% only a small proportion of the overall genetic risk has been accounted for, and to date only a limited number of genetic loci have been definitively implicated. We have identified recently through genetic and in vitro functional studies, a novel serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a rare risk factor for major mental disorders including schizophrenia. Now using the approach of in utero gene transfer we have discovered that Ulk4 plays a key modulatory role in corticogenesis. Knockdown of Ulk4 leads to significantly decreased cell proliferation in germinal zones and profound deficits in radial migration and neurite ramification. These abnormalities can be reversed successfully by Ulk4 gene supplementation. Ulk4 also regulated acetylation of α-tubulin, an important post-translational modification of microtubules. We conclude that Ulk4 plays an essential role in normal brain development and when defective, the risk of neurodevelopmental disorders such as schizophrenia is increased.
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