Hunter James Kelly Research Institute.
Department of Neurology.
J Neurosci. 2020 Aug 5;40(32):6165-6176. doi: 10.1523/JNEUROSCI.0951-20.2020. Epub 2020 Jul 8.
In the PNS, myelination occurs postnatally when Schwann cells (SCs) contact axons. Axonal factors, such as Neuregulin-1 Type III, trigger promyelinating signals that upregulate myelin genes. Neuregulin-1 Type III has been proposed to activate calcineurin signaling in immature SCs to initiate differentiation and myelination. However, little is known about the role of calcineurin in promyelinating SCs after birth. By creating a SC conditional KO of calcineurin B (CnB), we assessed the effects of ablation on peripheral myelination after birth in both male and female mice. Surprisingly, CnB mice have minimal myelination defects, no alteration of myelin thickness, and normal KROX20 expression. In contrast, we did find a unique role for calcineurin in SCs after nerve injury. Following nerve crush, CnB mice have slower degeneration of myelin compared with WT mice. Furthermore, absence of CnB in primary SCs delays clearance of myelin debris. SCs clear myelin via autophagy and recent literature has demonstrated that calcineurin can regulate autophagy via dephosphorylation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. We demonstrate that loss of CnB reduces autophagic flux in primary SCs, indicating a possible mechanism for impaired myelin clearance. In addition, ablation of CnB impairs TFEB translocation to the nucleus 3 d after crush, suggesting that calcineurin may regulate autophagy in SCs via TFEB activation. Together, our data indicate that calcineurin is not essential for myelination but has a novel role in myelin clearance after injury. Our data offer a novel mechanism for activation of autophagy after peripheral nerve injury. Efficient clearance of myelin after injury by Schwann cells is important for axonal regrowth and remyelination, which is one reason why the PNS is significantly better at recovery compared with the CNS. Improved understanding of myelin clearance allows for the identification of pathways that are potentially accessible to increase myelin clearance and improve remyelination and recovery. Finally, this paper clarifies the role of calcineurin in Schwann cells and myelination.
在周围神经系统中，施万细胞（SCs）与轴突接触后会发生出生后的髓鞘形成。轴突因子，如神经调节蛋白 1 型 III（Neuregulin-1 Type III），触发启动髓鞘形成的信号，上调髓鞘基因。神经调节蛋白 1 型 III 被提出可激活未成熟 SC 中的钙调神经磷酸酶信号，以启动分化和髓鞘形成。然而，关于钙调神经磷酸酶在出生后促进髓鞘形成的 SC 中的作用知之甚少。通过创建钙调神经磷酸酶 B（CnB）的 SC 条件性 KO，我们评估了该基因缺失对雄性和雌性小鼠出生后周围髓鞘形成的影响。令人惊讶的是，CnB 小鼠的髓鞘形成缺陷极小，没有髓鞘厚度改变，KROX20 表达正常。相比之下，我们确实发现钙调神经磷酸酶在神经损伤后的 SC 中有独特的作用。在神经挤压后，与 WT 小鼠相比，CnB 小鼠的髓鞘变性较慢。此外，初级 SC 中缺乏 CnB 会延迟髓鞘碎片的清除。SC 通过自噬清除髓鞘，最近的文献表明钙调神经磷酸酶可以通过去磷酸化转录因子 EB（TFEB）来调节自噬，TFEB 是溶酶体生物发生和自噬的主调控因子。我们证明，CnB 的缺失降低了初级 SC 中的自噬通量，表明这可能是髓鞘清除受损的一种机制。此外，挤压后 3d，CnB 的缺失会损害 TFEB 向核内的易位，表明钙调神经磷酸酶可能通过 TFEB 激活来调节 SC 中的自噬。总的来说，我们的数据表明钙调神经磷酸酶对于髓鞘形成不是必需的，但在损伤后的髓鞘清除中具有新的作用。我们的数据为周围神经损伤后自噬的激活提供了一种新的机制。损伤后由 Schwann 细胞有效清除髓鞘对于轴突再生和髓鞘形成很重要，这也是与中枢神经系统相比周围神经系统恢复能力更强的一个原因。对髓鞘清除的深入了解可以确定潜在可用于增加髓鞘清除、改善髓鞘形成和恢复的途径。最后，本文阐明了钙调神经磷酸酶在 Schwann 细胞和髓鞘形成中的作用。
