The deletion of dicer in mature myelinating glial cells causes progressive axonal degeneration but not overt demyelination in adult mice
The deletion of dicer in mature myelinating glial cells causes progressive axonal degeneration but not overt demyelination in adult mice
复制标题
成熟髓鞘神经胶质细胞中切丁酶的缺失会导致成年小鼠进行性轴突变性，但不会导致明显的脱髓鞘
作者：
Li, Tao;Wang, Jingjing;Xiao, Lan
中枢神经系统 (CNS) 中的髓鞘胶质细胞 (MGC)、少突胶质细胞 (OL) 和周围神经系统 (PNS) 中的雪旺细胞 (SC) 产生隔离轴突的髓鞘。成年期髓鞘形成完成后，需要独立于髓磷脂的 MGC 功能来支持轴突存活，但其潜在机制仍不清楚。 Dicer 是一种关键酶，负责生成功能性 micro-RNA (miRNA)。尽管 Dicer 在启动髓鞘形成中很重要，但 Dicer 在成熟 MGC 中的作用仍不清楚。在这里，通过给予他莫昔芬，Dicer 在 2 个月大的小鼠 (PLP-CreERT; Dicer fl/fl) 的成熟 MGC 中被特异性删除。在 Dicer 条件敲除小鼠中观察到进行性运动功能障碍，重组后 3 个月表现出后肢共济失调，并在 5 个月内恶化为瘫痪。周围神经的大量轴突变性/萎缩是造成这种现象的原因，但在中枢神经系统或三七总神经系统中均未观察到明显的脱髓鞘。与 PNS 相比，在这些动物的 CNS 中没有观察到轴突变性的迹象。我们在出生后第 5 天在 NG2-CreERT 中诱导了少突胶质细胞中的 Dicer 缺失； Dicer fl/fl 小鼠评估 OL 中的 Dicer 表达是否对轴突存活至关重要。少突胶质细胞中 Dicer 缺失并未导致 7 个月大时的运动功能障碍。在中枢神经系统中未观察到轴突萎缩或脱髓鞘。根据我们的结果，SC 中的 Dicer 表达对于维持成人 PNS 中轴突的完整性是必需的，而 Dicer 对于维持 MGC 中的髓鞘是可有可无的。
Myelinating glial cells (MGCs), oligodendrocytes (OLs) in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS), generate myelin sheaths that insulate axons. After myelination is completed in adulthood, MGC functions independent from myelin are required to support axon survival, but the underlying mechanisms are still unclear. Dicer is a key enzyme that is responsible for generating functional micro‐RNAs (miRNAs). Despite the importance of Dicer in initiating myelination, the role of Dicer in mature MGCs is still unclear. Here, Dicer was specifically deleted in mature MGCs in 2‐month old mice (PLP‐CreERT; Dicer fl/fl) by tamoxifen administration. Progressive motor dysfunction was observed in the Dicer conditional knockout mice, which displayed hind limb ataxia at 3 months post recombination that deteriorated into paralysis within 5 months. Massive axonal degeneration/atrophy in peripheral nerves was responsible for this phenomenon, but overt demyelination was not observed in either the CNS or PNS. In contrast to the PNS, signs of axonal degeneration were not observed in the CNS of these animals. We induced a Dicer deletion in oligodendroglia at postnatal day 5 in NG2‐CreERT; Dicer fl/fl mice to evaluate whether Dicer expression in OLs is essential for axonal survival. Dicer deletion in oligodendroglia did not cause motor dysfunction at the age of 7 months. Neither axonal atrophy nor demyelination was observed in the CNS. Based on our results, Dicer expression in SCs is required to maintain axon integrity in adult PNS, and Dicer is dispensable for maintaining myelin sheaths in MGCs.