Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities.
Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities.
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DOI：
10.1016/j.celrep.2012.11.017
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发表时间：
2012-12-27
期刊：
影响因子：
8.8
通讯作者：
Keays DA
中科院分区：
文献类型：
--
作者：
Breuss M;Heng JI;Poirier K;Tian G;Jaglin XH;Qu Z;Braun A;Gstrein T;Ngo L;Haas M;Bahi-Buisson N;Moutard ML;Passemard S;Verloes A;Gressens P;Xie Y;Robson KJ;Rani DS;Thangaraj K;Clausen T;Chelly J;Cowan NJ;Keays DA
哺乳动物皮质的形成需要神经元的产生、迁移和分化。微管细胞骨架在这些细胞过程中发挥的重要作用反映在各种微管蛋白亚型突变会导致不同的神经发育疾病，包括无脑(TUBA1A)、多微回(TUBA1A、TUBB2B、TUBB3)和眼球运动障碍(TUBB3)。在这里，我们证明了TUBB5在小鼠的神经源性前体细胞中表达，并且它在体内的枯竭扰乱了前体细胞的细胞周期，改变了迁移神经元的位置。我们报告了三例具有结构性脑异常的小头症患者，其TUBB5基因(M299V、V353I和E401K)发生了新的突变。这些突变的蛋白质以不同的方式影响微管蛋白异二聚体的伴侣依赖性组装，扰乱体内的神经源性分裂和/或迁移。我们的结果为微管蛋白基因家族的功能谱提供了洞察力，特别是涉及TUBB5在胚胎神经发生和小头畸形中的作用。►β微管蛋白TUBB5在发育中的小鼠和人类皮质中高表达►在体内敲除TUBB5扰乱细胞周期并改变神经元的定位►突变导致小头症与人类基底节畸形►TUBB5突变以不同方式影响伴侣介导的微管蛋白折叠皮质的形成需要神经元的生成、迁移和分化。虽然特定的微管蛋白亚型与有丝分裂后事件有关，但那些介导神经发生的亚型仍不清楚。在这里，凯斯和他的同事们报告说，β-微管蛋白基因TUBB5的突变会导致小头畸形。他们表明，该基因在神经元前体细胞中高度表达，其在体内的缺失扰乱了细胞周期，改变了神经元的迁移。这项工作为微管蛋白基因家族的功能谱提供了洞察力。
The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly. ► The β-tubulin Tubb5 is highly expressed in the developing mouse and human cortex ► In vivo knockdown of Tubb5 perturbs the cell cycle and alters neuronal positioning ► Mutations in TUBB5 cause microcephaly with dysmorphic basal ganglia in humans ► TUBB5 mutations affect chaperone-mediated tubulin folding in different ways The formation of the cortex requires the generation, migration, and differentiation of neurons. While specific tubulin isotypes have been implicated in postmitotic events, those that mediate neurogenesis remain unknown. Here, Keays and colleagues report that mutations in the β-tubulin gene, TUBB5, cause microcephaly. They show that this gene is highly expressed in neuronal progenitors, and its depletion in vivo perturbs the cell cycle and alters neuronal migration. This work provides insight into the functional repertoire of the tubulin gene family.
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