Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis.
Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis.
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DOI：
10.1016/j.neuron.2016.03.027
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发表时间：
2016-05-04
期刊：
影响因子：
16.2
通讯作者：
Jan YN
中科院分区：
文献类型：
--
作者：
Ori-McKenney KM;McKenney RJ;Huang HH;Li T;Meltzer S;Jan LY;Vale RD;Wiita AP;Jan YN
树突状树突模式是遗传疾病如唐氏综合症（DS）和自闭症谱系障碍（ASD）的一致解剖学相关性。在树突发育异常的筛选中，我们发现Minibrain(MNB)/DYRK1a是一种与DS和ASD有关的激酶，可以调节微管细胞骨架。我们发现MNB是通过控制微管生长来建立末端树突的长度和细胞骨架组成所必需的。改变MNB水平会破坏树突形态，扰乱神经元电生理活动，导致幼虫机械感觉缺陷。利用体内和体外方法，我们发现了一种分子途径，通过MNB直接磷酸化β-微管蛋白抑制微管蛋白聚合，这一功能在哺乳动物DYRK1a中是保守的。我们的研究结果表明，MNB/DYRK1a对微管动力学的磷酸化调控对树突模式和神经元功能至关重要，揭示了一种以前未被发现的神经元翻译后微管调控模式，并揭示了DS和asd相关激酶的保守途径。
Dendritic arborization patterns are consistent anatomical correlates of genetic disorders such as Down syndrome (DS) and autism spectrum disorders (ASD). In a screen for abnormal dendrite development, we identified Minibrain(MNB)/DYRK1a, a kinase implicated in DS and ASD, as a regulator of the microtubule cytoskeleton. We show that MNB is necessary to establish the length and cytoskeletal composition of terminal dendrites by controlling microtubule growth. Altering MNB levels disrupts dendrite morphology and perturbs neuronal electrophysiological activity, resulting in larval mechanosensation defects. Using in vivo and in vitro approaches, we uncover a molecular pathway whereby direct phosphorylation of β-tubulin by MNB inhibits tubulin polymerization, a function that is conserved for mammalian DYRK1a. Our results demonstrate that phospho-regulation of microtubule dynamics by MNB/DYRK1a is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of post-translational microtubule regulation in neurons and uncovering a conserved pathway for a DS- and ASD-associated kinase.