Department of Biological Sciences, University of Wisconsin-Milwaukee; Milwaukee, Wisconsin, United States of America.
Department of Molecular and Cellular Biology, University of California, Davis, California, United States of America.
PLoS Genet. 2022 Nov 21;18(11):e1010521. doi: 10.1371/journal.pgen.1010521. eCollection 2022 Nov.
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.
一个巨大的 KASH 蛋白家族，包括线虫 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，细胞器锚定在轴突发育中的作用也知之甚少。在这里，我们报告 ANC-1 与 SLT-1 细胞外导向线索一起作用以极化 ALM 轴突生长。ANC-1 的这种作用是其较长的 ANC-1A 和 ANC-1C 异构体特有的，这表明它在机制上与先前描述的 ANC-1 作用不同。我们发现 ANC-1 对于将一群线粒体定位于近端轴突的底部是必需的。此外，遗传和药理学研究表明，ANC-1 与线粒体一起作用以促进 ALM 轴突生长的极化。这些观察结果揭示了一种机制，通过该机制，ANC-1 通过线粒体起作用，以响应 SLT-1 来极化轴突生长。
