Adenomatous polyposis coli regulates oligodendroglial development.
Adenomatous polyposis coli regulates oligodendroglial development.
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DOI：
10.1523/jneurosci.3467-12.2013
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发表时间：
2013-02-13
期刊：
影响因子：
--
通讯作者：
Guo F
中科院分区：
文献类型：
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作者：
Lang J;Maeda Y;Bannerman P;Xu J;Horiuchi M;Pleasure D;Guo F
肠道肿瘤抑制基因腺瘤性息肉病(APC)的表达及其在少突胶质细胞谱系中的作用尚不清楚。我们发现，在毒素诱导的、遗传的或自身免疫性脱髓鞘小鼠模型中，在正常髓鞘形成和重新髓鞘形成过程中，免疫反应活跃的APC在少突胶质细胞谱系中被一过性诱导。使用Cre/loxP系统有条件地去除少突胶质细胞系中的APC，我们确定APC促进了少突胶质前体细胞(OPC)的增殖，并以一种细胞自主的方式对少突胶质细胞的分化至关重要。在出生后早期，双等位基因APC破坏导致β-连环蛋白移位到细胞核内，并上调β-连环蛋白介导的WnT信号，但在成年少突胶质细胞系细胞中不出现。APC或CTNNB1(编码β-连环蛋白的基因)的条件消融以及APC和CTNNB1的同时条件消融的结果表明，β-连环蛋白对于出生后的少突胶质细胞的分化是必不可少的，APC的一个等位基因缺失不足以扰乱β-连环蛋白介导的少突胶质细胞系细胞的WNT信号转导，APC通过β-连环蛋白不依赖的机制以及β-连环蛋白依赖的机制来调节少突胶质细胞的分化。微阵列数据的基因本体论分析表明，β-连环蛋白非依赖性机制涉及细胞骨架的APC调节，这一结果与神经前体中已建立的APC功能相一致，也与我们观察到的APC缺失的OPC在体内发展更少、更短的过程相一致。综上所述，我们的数据支持这一假说，即APC通过β连环蛋白依赖和额外的β连环蛋白不依赖的机制来调节少突胶质细胞的分化。
The expression of the gut tumor suppressor gene adenomatous polyposis coli (Apc) and its’ role in the oligodendroglial lineage are poorly understood. We found that immunoreactive APC is transiently induced in the oligodendroglial lineage during both normal myelination and remyelination following toxin-induced, genetic or autoimmune demyelination murine models. Using the Cre/loxP system to conditionally ablate APC from the oligodendroglial lineage, we determined that APC enhances proliferation of oligodendroglial progenitor cells (OPCs) and is essential for oligodendrocyte differentiation in a cell-autonomous manner. Biallelic Apc disruption caused translocation of β-catenin into the nucleus and up-regulated β-catenin-mediated Wnt signaling in early postnatal but not adult oligodendroglial lineage cells. The results of conditional ablation of Apc or Ctnnb1 (the gene encoding β-catenin), and of simultaneous conditional ablation of Apc and Ctnnb1, revealed that β-catenin is dispensable for postnatal oligodendroglial differentiation, that Apc one-allele deficiency is not sufficient to dysregulate β-catenin-mediated Wnt signaling in oligodendroglial lineage cells, and that APC regulates oligodendrocyte differentiation through β-catenin-independent, as well as β-catenin-dependent mechanisms. Gene ontology analysis of microarray data suggested that the β-catenin-independent mechanism involves APC regulation of the cytoskeleton, a result compatible with established APC functions in neural precursors and with our observation that Apc-deleted OPCs develop fewer, shorter processes in vivo. Together, our data support the hypothesis that APC regulates oligodendrocyte differentiation through both β-catenin-dependent and additional β-catenin-independent mechanisms.