A vital role of tubulin-tyrosine-ligase for neuronal organization
A vital role of tubulin-tyrosine-ligase for neuronal organization
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DOI：
10.1073/pnas.0409626102
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发表时间：
2005-05-31
影响因子：
11.1
通讯作者：
Wehland, J
中科院分区：
文献类型：
--
作者：
Erck, C;Peris, L;Wehland, J
微管蛋白经历脱酪氨酸/酪氨酸化的特殊循环，其中α-微管蛋白的C-末端酪氨酸被羧肽酶循环去除并被微管蛋白-酪氨酸-连接酶（TTL）重新连接。这种酪氨酸化循环在进化中是保守的，但其生理重要性尚不清楚。在这里，我们发现，小鼠的TTL抑制导致围产期死亡。少量的酪氨酸化（Tyr-）微管蛋白存在于TTL无效组织中，主要存在于分裂的TTL无效细胞中，其中它起源于微管蛋白合成，但它缺乏有丝分裂后的TTL无效细胞，例如神经元，这显然是有害的，因为早期死亡在TTL无效小鼠中至少部分是由于神经元网络的解体，包括皮质-丘脑回路的破坏。相关地，培养的TTL空神经元显示形态发生异常，包括轴突生长和过早轴突分化的加速和不稳定的时间过程。这些异常可能涉及CLIP 170的错误定位，我们发现缺乏TTL空神经元的轴突延伸和生长锥。我们的研究结果表明，TTL的神经组织的重要作用，并建议适当的控制神经突延伸的酪氨酸微管蛋白的要求。
Tubulin is subject to a special cycle of detyrosination/tyrosination in which the C-terminal tyrosine of alpha-tubulin is cyclically removed by a carboxypeptidase and readded by a tubulin-tyrosine-ligase (TTL). This tyrosination cycle is conserved in evolution, yet its physiological importance is unknown. Here, we find that TTL suppression in mice causes perinatal death. A minor pool of tyrosinated (Tyr-)tubulin persists in TTL null tissues, being present mainly in dividing TTL null cells where it originates from tubulin synthesis, but it is lacking in postmitotic TTL null cells such as neurons, which is apparently deleterious because early death in TTL null mice is, at least in part, accounted for by a disorganization of neuronal networks, including a disruption of the cortico-thalamic loop. Correlatively, cultured TTL null neurons display morphogenetic anomalies including an accelerated and erratic time course of neurite outgrowth and a premature axonal differentiation. These anomalies may involve a mislocalization of CLIP170, which we find lacking in neurite extensions and growth cones of TTL null neurons. Our results demonstrate a vital role of TTL for neuronal organization and suggest a requirement of Tyr-tubulin for proper control of neurite extensions.