Ori-McKenney Kassandra M, McKenney Richard J, Huang Hector H, Li Tun, Meltzer Shan, Jan Lily Yeh, Vale Ronald D, Wiita Arun P, Jan Yuh Nung
Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Neuron. 2016 May 4;90(3):551-63. doi: 10.1016/j.neuron.2016.03.027. Epub 2016 Apr 21.
Dendritic arborization patterns are consistent anatomical correlates of genetic disorders such as Down syndrome (DS) and autism spectrum disorders (ASDs). In a screen for abnormal dendrite development, we identified Minibrain (MNB)/DYRK1a, a kinase implicated in DS and ASDs, 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 phosphoregulation of microtubule dynamics by MNB/DYRK1a is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of posttranslational microtubule regulation in neurons and uncovering a conserved pathway for a DS- and ASD-associated kinase.
树突分支模式是诸如唐氏综合征（DS）和自闭症谱系障碍（ASD）等遗传疾病一致的解剖学关联特征。在一项针对异常树突发育的筛选中，我们鉴定出小脑海绵体（MNB）/双特异性酪氨酸磷酸化调节激酶1A（DYRK1a），一种与DS和ASD相关的激酶，作为微管细胞骨架的调节因子。我们发现MNB对于通过控制微管生长来确定终末树突的长度和细胞骨架组成是必需的。改变MNB水平会破坏树突形态并扰乱神经元电生理活动，导致幼虫机械感觉缺陷。使用体内和体外方法，我们揭示了一条分子途径，通过该途径MNB对β-微管蛋白的直接磷酸化抑制微管蛋白聚合，这一功能在哺乳动物DYRK1a中是保守的。我们的结果表明，MNB/DYRK1a对微管动力学的磷酸化调节对于树突模式形成和神经元功能至关重要，揭示了神经元中一种以前未被识别的翻译后微管调节模式，并揭示了一条与DS和ASD相关激酶的保守途径。
