The E3 Ligase Mind Bomb-1 (Mib1) Modulates Delta-Notch Signaling to Control Neurogenesis and Gliogenesis in the Developing Spinal Cord
The E3 Ligase Mind Bomb-1 (Mib1) Modulates Delta-Notch Signaling to Control Neurogenesis and Gliogenesis in the Developing Spinal Cord
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DOI：
10.1074/jbc.m112.398263
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发表时间：
2013-01-25
影响因子：
4.8
通讯作者：
Song, Mi-Ryoung
中科院分区：
文献类型：
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作者：
Kang, Kyungjoon;Lee, Donghoon;Song, Mi-Ryoung
Notch信号通路是中枢神经系统发育过程中神经元和神经胶质细胞特化所必需的。Mind bomb-1（Mib 1）是一种E3遍在蛋白连接酶，可遍在蛋白化并促进Notch配体的内吞作用。虽然Mib 1对于传递Notch信号是必不可少的，但仍不清楚它是否是发育中脊髓中Notch配体活性的主要调节因子。在Mib 1条件性基因敲除小鼠中，我们观察到脊髓祖细胞的耗竭、神经元的过早分化和V2中间神经元的不平衡特化，所有这些都模拟了传统的Notch表型。与此一致，在Mib 1的情况下祖细胞的减少导致星形胶质细胞和少突胶质细胞的损失。使用药物诱导系统晚期去除Mib 1抑制胶质细胞分化，表明Mib 1继续在主要指定用于胶质细胞生成的晚期祖细胞的形成中发挥作用。最后，Mib 1或Mib 1缺失突变体的错误表达表明，Mib 1的环结构域是鸡神经管中V2中间神经元的规范所必需的。总之，这些发现表明，Mib 1是提供Notch配体活性所需的信号发送细胞的主要成分，用于指定脊髓中的神经元和神经胶质细胞。
The Notch signaling pathway is essential for neuronal and glial specification during CNS development. Mind bomb-1 (Mib1) is an E3 ubiquitin ligase that ubiquitinates and promotes the endocytosis of Notch ligands. Although Mib1 is essential for transmitting the Notch signal, it is still unclear whether it is a primary regulator of Notch ligand activity in the developing spinal cord. In Mib1 conditional knock-out mice, we observed depletion of spinal progenitors, premature differentiation of neurons, and unbalanced specification of V2 interneurons, all of which mimic the conventional Notch phenotype. In agreement with this, the reduction of progenitors in the absence of Mib1 led to a loss of both astrocytes and oligodendrocytes. Late removal of Mib1 using a drug-inducible system suppressed glial differentiation, suggesting that Mib1 continues to play a role in the formation of late progenitors mainly designated for gliogenesis. Finally, misexpression of Mib1 or Mib1 deletion mutants revealed that the ring domain of Mib1 is required for the specification of V2 interneurons in the chick neural tube. Together, these findings suggest that Mib1 is a major component of the signal-sending cells required to provide Notch ligand activity for specifying neurons and glia in the spinal cord.