The ANC-1 (Nesprin-1/2) organelle-anchoring protein functions through mitochondria to polarize axon growth in response to SLT-1.
The ANC-1 (Nesprin-1/2) organelle-anchoring protein functions through mitochondria to polarize axon growth in response to SLT-1.
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DOI：
10.1371/journal.pgen.1010521
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发表时间：
2022-11
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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一个巨大的KASH蛋白家族，包括C.线虫ANC-1和哺乳动物Nesprin-1和-2参与细胞器锚定，并与多种神经发育障碍有关，包括自闭症、双相情感障碍和精神分裂症。然而，人们对这些蛋白质在神经元中的功能知之甚少。此外，轴突发育中细胞器锚定的作用知之甚少。在这里，我们报告说，ANC-1的功能与ESTA-1细胞外的指导线索，以MATERIALM轴突生长。ANC-1的这种作用是其较长的ANC-1A和ANC-1C同种型所特有的，这表明它在机制上不同于先前描述的ANC-1的作用。我们发现ANC-1是将线粒体簇定位到近端轴突底部所必需的。此外，遗传和药理学研究表明ANC-1与线粒体一起发挥作用，以促进ALM轴突生长的极化。这些观察结果揭示了ANC-1通过线粒体响应ANC-1的轴突生长发挥作用的机制。大脑由神经元网络组成，每个神经元延伸出一个与其他神经元连接的轴突。这些轴突连接的改变被认为会导致自闭症、躁郁症和精神分裂症等大脑疾病。这些疾病的风险增加了线粒体的改变，线粒体是神经元内的一种细胞器，需要产生能量和信号，促进轴突连接的正常发育。虽然线粒体对正常轴突发育至关重要，但介导轴突内线粒体的正确定位和功能的机制还不清楚。在这里，我们确定了一种蛋白质，促进正确的定位线粒体的基础上的轴突。这种蛋白质的破坏导致线粒体定位缺陷，并导致轴突发育缺陷。这种蛋白质的人类同源物的改变与大脑疾病有关，这表明了这些疾病如何出现的可能解释。
A family of giant KASH proteins, including C. elegans ANC-1 and mammalian Nesprin-1 and -2, are involved in organelle anchoring and are associated with multiple neurodevelopmental disorders including autism, bipolar disorder, and schizophrenia. However, little is known about how these proteins function in neurons. Moreover, the role of organelle anchoring in axon development is poorly understood. Here, we report that ANC-1 functions with the SLT-1 extracellular guidance cue to polarize ALM axon growth. This role for ANC-1 is specific to its longer ANC-1A and ANC-1C isoforms, suggesting that it is mechanistically distinct from previously described roles for ANC-1. We find that ANC-1 is required for the localization of a cluster of mitochondria to the base of the proximal axon. Furthermore, genetic and pharmacological studies indicate that ANC-1 functions with mitochondria to promote polarization of ALM axon growth. These observations reveal a mechanism whereby ANC-1 functions through mitochondria to polarize axon growth in response to SLT-1. The brain is comprised of a network of neurons, with each neuron extending a single axon that makes connections with other neurons. Alterations in these axonal connections are thought to cause brain disorders such as autism, bipolar disorder, and schizophrenia. The risk of these disorders is increased by alterations in mitochondria, an organelle within neurons that is needed for the production of energy and signals that promote normal development of axonal connections. Although mitochondria are critical for normal axon development, the mechanisms that mediate the correct localization and function of mitochondria within axons are not well understood. Here, we identify a protein that promotes the correct localization of mitochondria to the base of the axon. Disruption of this protein causes defects in mitochondria localization and causes defects in axon development. Alterations in the human homolog of this protein have been associated with brain disorders, suggesting a possible explanation of how these disorders arise.
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影响因子：
30.8
作者：
Krumm, Niklas;Turner, Tychele N.;Baker, Carl;Vives, Laura;Mohajeri, Kiana;Witherspoon, Kali;Raja, Archana;Coe, Bradley P.;Stessman, Holly A.;He, Zong-Xiao;Leal, Suzanne M.;Bernier, Raphael;Eichler, Evan E.
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影响因子：
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Wigler, Michael
影响因子：
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Adler, CE;Fetter, RD;Bargmann, CI
通讯作者：
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影响因子：
30.8
作者：
Gros-Louis, Francois;Dupre, Nicolas;Rouleau, Guy A.
通讯作者：
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