Novel α-tubulin mutation disrupts neural development and tubulin proteostasis.
Novel α-tubulin mutation disrupts neural development and tubulin proteostasis.
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DOI：
10.1016/j.ydbio.2015.11.022
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发表时间：
2016-01-15
影响因子：
2.7
通讯作者：
Moore JK
中科院分区：
文献类型：
--
作者：
Gartz Hanson M;Aiken J;Sietsema DV;Sept D;Bates EA;Niswander L;Moore JK
微管细胞骨架的突变与发育过程中的认知和运动缺陷以及成年人的神经退化有关。这些突变如何影响微管，以及这种突变如何改变神经元水平的功能是一个重要的研究领域。在小鼠的正向遗传筛查中，我们发现了Tuba1aα-微管蛋白中的一个错义突变，它扰乱了皮质和运动神经元的发育。纯合子突变小鼠表现出皮质发育不全，这让人想起人类的小管蛋白病变。运动神经元不能支配四肢的目标肌肉，并在近端的目标显示出突触缺陷。为了直接检测对微管蛋白功能的影响，我们在萌芽酵母中创建了类似的α-微管蛋白亚型突变。这些突变使酵母细胞对微管压力敏感，包括解聚药物和低温。此外，我们发现突变的α-微管蛋白从细胞裂解液和微管中被耗尽，从而改变了α-微管蛋白亚型的比例。微管结合辅助因子抑制突变的影响，表明这些辅助因子在调节α-微管蛋白池的质量中发挥重要作用。总之，我们的结果为Tuba1a的功能、调节微管蛋白平衡的机制以及这些机制如何导致神经缺陷提供了新的见解。
Mutations in the microtubule cytoskeleton are linked to cognitive and locomotor defects during development, and neurodegeneration in adults. How these mutations impact microtubules, and how this alters function at the level of neurons is an important area of investigation. Using a forward genetic screen in mice, we identified a missense mutation in Tuba1a α-tubulin that disrupts cortical and motor neuron development. Homozygous mutant mice exhibit cortical dysgenesis reminiscent of human tubulinopathies. Motor neurons fail to innervate target muscles in the limbs and show synapse defects at proximal targets. To directly examine effects on tubulin function, we created analogous mutations in the α-tubulin isotypes in budding yeast. These mutations sensitize yeast cells to microtubule stresses including depolymerizing drugs and low temperatures. Furthermore, we find that mutant α-tubulin is depleted from the cell lysate and from microtubules, thereby altering ratios of α-tubulin isotypes. Tubulin-binding cofactors suppress the effects of the mutation, indicating an important role for these cofactors in regulating the quality of the α-tubulin pool. Together, our results give new insights into the functions of Tuba1a, mechanisms for regulating tubulin proteostasis, and how compromising these may lead to neural defects.