Vertebrate nervous systems use the axon initial segment (AIS) to initiate action potentials and maintain neuronal polarity. The microtubule-associated protein tripartite motif containing 46 (TRIM46) was reported to regulate axon specification, AIS assembly, and neuronal polarity through the bundling, or fasciculation, of microtubules in the proximal axon. However, these claims are based on TRIM46 knockdown in cultured neurons. To investigate TRIM46 function in vivo, we examined male and female TRIM46 knockout mice. Contrary to previous reports, we find that TRIM46 is dispensable for axon specification and AIS formation. TRIM46 knockout mice are viable, have normal behavior, and have normal brain structure. Thus, TRIM46 is not required for AIS formation, axon specification, or nervous system function. However, we confirm that TRIM46 is required for microtubule fasciculation. We also show TRIM46 enrichment in the first ∼100 μm of axon occurs independently of ankyrinG (AnkG) in vivo, although AnkG is required to restrict TRIM46 only to the AIS. Our results highlight the need for further investigation of the mechanisms by which the AIS and microtubules interact to shape neuronal structure and function.Significance statement A healthy nervous system requires the polarization of neurons into structurally and functionally distinct compartments, which depends on both the axon initial segment (AIS) and the microtubule cytoskeleton. In contrast to previous reports, we show that the microtubule-associated protein TRIM46 is required for microtubule fasciculation, but not for axon specification or AIS formation in mice. Our results emphasize the need for further investigation of the mechanisms by which the AIS and microtubules interact to shape neuronal structure and function.

中文翻译：

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TRIM46 是体内微管束颤所必需的，但不是轴突规范或轴突初始片段形成所必需的。


脊椎动物神经系统使用轴突起始段（AIS）来启动动作电位并维持神经元极性。据报道，含有 46 (TRIM46) 的微管相关蛋白三联基序通过近端轴突中微管的成束或成束来调节轴突规范、AIS 组装和神经元极性。然而，这些说法是基于培养神经元中 TRIM46 的敲低。为了研究 TRIM46 的体内功能，我们检查了雄性和雌性 TRIM46 敲除小鼠。与之前的报道相反，我们发现 TRIM46 对于轴突规范和 AIS 形成是可有可无的。 TRIM46 基因敲除小鼠具有存活能力，具有正常行为，并且具有正常的大脑结构。因此，TRIM46 不是 AIS 形成、轴突规范或神经系统功能所必需的。然而，我们确认 TRIM46 是微管束颤所必需的。我们还表明 TRIM46 在轴突前 ∼100 μm 的富集独立于体内锚蛋白 G (AnkG) 发生，尽管 AnkG 需要将 TRIM46 限制在 AIS 上。我们的结果强调需要进一步研究 AIS 和微管相互作用以塑造神经元结构和功能的机制。 意义陈述 健康的神经系统需要将神经元极化成结构和功能不同的区室，这取决于轴突初始节段（AIS）和微管细胞骨架。与之前的报道相反，我们发现微管相关蛋白 TRIM46 是微管束颤所必需的，但对于小鼠中的轴突规范或 AIS 形成不是必需的。我们的结果强调需要进一步研究 AIS 和微管相互作用塑造神经元结构和功能的机制。