Human TUBB3 Mutations Disrupt Netrin Attractive Signaling.
Human TUBB3 Mutations Disrupt Netrin Attractive Signaling.
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DOI：
10.1016/j.neuroscience.2018.01.046
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发表时间：
2018-03-15
期刊：
影响因子：
3.3
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Huang H;Yang T;Shao Q;Majumder T;Mell K;Liu G
人类TUBB3基因的杂合错义突变会导致一系列脑部畸形，这些畸形与轴突导向、神经元迁移及分化缺陷相关。然而，突变相关轴突导向异常背后的分子机制尚不清楚。近期研究表明，经典导向信号分子netrin - 1可诱导TUBB3与结直肠癌缺失基因（DCC，一种netrin受体）相互作用。此外，netrin - 1诱导的轴突生长、分支及路径寻找需要TUBB3的参与。在此，我们提供证据表明，TUBB3突变会损害发育中神经系统内的netrin / DCC信号传导。与野生型TUBB3相比，大多数TUBB3突变体（12个中有8个）与DCC的相互作用显著降低。在原代神经元的生长锥中，TUBB3突变体R262C和A302V与DCC的亚细胞共定位减少。在原代神经元中，netrin - 1可增强内源性DCC与野生型人类TUBB3的相互作用，但对R262C或A302V则无此作用。在表达野生型TUBB3的原代神经元中，netrin - 1还可增加DCC与聚合微管（MTs）的共沉降，但对表达R262C或A302V的原代神经元则无此效果。无论是R262C还是A302V的表达，不仅在体外会抑制netrin - 1诱导的神经突生长、分支及吸引，而且在鸡胚中会导致脊髓连合轴突（CA）投射和路径寻找缺陷。我们的研究揭示，TUBB3错义突变会特异性地破坏netrin / DCC介导的吸引信号传导。
Heterozygous missense mutations in human TUBB3 gene result in a spectrum of brain malformations associated with defects in axon guidance, neuronal migration and differentiation. However, the molecular mechanisms underlying mutation-related axon guidance abnormalities are unclear. Recent studies have shown that netrin-1, a canonical guidance cue, induced the interaction of TUBB3 with the netrin receptor deleted in colorectal cancer (DCC). Furthermore, TUBB3 is required for netrin-1-induced axon outgrowth, branching and pathfinding. Here, we provide evidence that TUBB3 mutations impair netrin/DCC signaling in the developing nervous system. The interaction of DCC with most TUBB3 mutants (eight out of twelve) is significantly reduced compared to the wild type TUBB3. TUBB3 mutants R262C and A302V exhibit decreased subcellular colocalization with DCC in the growth cones of primary neurons. Netrin-1 increases the interaction of endogenous DCC with wild type human TUBB3, but not R262C or A302V, in primary neurons. Netrin-1 also increases co-sedimentation of DCC with polymerized microtubules (MTs) in primary neurons expressing the wild type TUBB3, but not R262C or A302V. Expression of either R262C or A302V not only suppresses netrin-1-induced neurite outgrowth, branching and attraction in vitro, but also causes defects in spinal cord commissural axon (CA) projection and pathfinding in ovo. Our study reveals that missense TUBB3 mutations specifically disrupt netrin/DCC-mediated attractive signaling.
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影响因子：
5.3
作者：
Dent, EW;Barnes, AM;Kalil, K
通讯作者：
Kalil, K
影响因子：
64.5
作者：
Graef, IA;Wang, F;Crabtree, GR
通讯作者：
Crabtree, GR
DOI：
10.1242/dev.023739
发表时间：
2008-12
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
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通讯作者：
Kidd T
影响因子：
64.5
作者：
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通讯作者：
Tessier-Lavigne, M
影响因子：
16.2
作者：
Deiner, MS;Kennedy, TE;Sretavan, DW
通讯作者：
Sretavan, DW