Instituto de Investigaciones Biomédicas de Madrid Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28029, Spain.
J Biol Chem. 2010 Jan 8;285(2):1343-57. doi: 10.1074/jbc.M109.024703. Epub 2009 Nov 10.
In order for neurons to perform their function, they must establish a highly polarized morphology characterized, in most of the cases, by a single axon and multiple dendrites. Herein we find that the evolutionarily conserved protein Kidins220 (kinase D-interacting substrate of 220-kDa), also known as ARMS (ankyrin repeat-rich membrane spanning), a downstream effector of protein kinase D and neurotrophin and ephrin receptors, regulates the establishment of neuronal polarity and development of dendrites. Kidins220/ARMS gain and loss of function experiments render severe phenotypic changes in the processes extended by hippocampal neurons in culture. Although Kidins220/ARMS early overexpression hinders neuronal development, its down-regulation by RNA interference results in the appearance of multiple longer axon-like extensions as well as aberrant dendritic arbors. We also find that Kidins220/ARMS interacts with tubulin and microtubule-regulating molecules whose role in neuronal morphogenesis is well established (microtubule-associated proteins 1b, 1a, and 2 and two members of the stathmin family). Importantly, neurons where Kidins220/ARMS has been knocked down register changes in the phosphorylation activity of MAP1b and stathmins. Altogether, our results indicate that Kidins220/ARMS is a key modulator of the activity of microtubule-regulating proteins known to actively regulate neuronal morphogenesis and suggest a mechanism by which it contributes to control neuronal development.
为了使神经元发挥其功能，它们必须建立一种高度极化的形态，这种形态在大多数情况下表现为一个单一的轴突和多个树突。在此，我们发现进化上保守的蛋白 Kidins220（蛋白激酶 D 相互作用的底物 220kDa），也称为 ARMS（富含锚蛋白重复的跨膜），是蛋白激酶 D 和神经营养因子及 ephrin 受体的下游效应物，调节神经元极性的建立和树突的发育。Kidins220/ARMS 的功能获得和功能丧失实验导致培养的海马神经元延伸的过程中出现严重的表型变化。虽然 Kidins220/ARMS 的早期过表达会阻碍神经元的发育，但通过 RNA 干扰下调其表达会导致出现多个更长的轴突样延伸和异常的树突分支。我们还发现 Kidins220/ARMS 与微管和微管调节分子相互作用，这些分子在神经元形态发生中的作用已经得到很好的证实（微管相关蛋白 1b、1a 和 2 以及 stathmin 家族的两个成员）。重要的是，下调 Kidins220/ARMS 的神经元改变了 MAP1b 和 stathmins 的磷酸化活性。总之，我们的研究结果表明，Kidins220/ARMS 是微管调节蛋白活性的关键调节剂，这些蛋白已知可积极调节神经元形态发生，并提出了它有助于控制神经元发育的机制。
