Severe Alterations of Cerebellar Cortical Development after Constitutive Activation of Wnt Signaling in Granule Neuron Precursors
Severe Alterations of Cerebellar Cortical Development after Constitutive Activation of Wnt Signaling in Granule Neuron Precursors
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DOI：
10.1128/mcb.05718-11
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发表时间：
2011-08-01
影响因子：
5.3
通讯作者：
Schueller, Ulrich
中科院分区：
文献类型：
--
作者：
Lorenz, Andreas;Deutschmann, Markus;Schueller, Ulrich
Wnt/β-连环蛋白信号通路在早期后脑形成中起着至关重要的作用，其组成性活性与人类髓母细胞瘤（一种儿童后颅窝恶性肿瘤）的亚群相关。然而，Wnt/β-catenin信号在小脑发育过程中的确切功能仍然是难以捉摸的。我们产生了Math 1-cre：：Apc（Fl/Fl）小鼠，其具有条件性敲除结肠腺瘤息肉病（Apc）基因，该基因在小脑颗粒神经元前体中显示出Wnt/β-连环蛋白信号传导的组成性活性。这些小鼠表现出正常的存活，没有任何肿瘤形成，但小脑明显较小，其皮质组织结构完全破坏。Wnt/beta-catenin信号通路的激活导致小脑颗粒神经元前体细胞在体外和体内的增殖和过早分化受到严重抑制。突变小鼠几乎没有形成内部颗粒层，浦肯野神经元的分层是混乱的。临床上，这些小鼠表现出显著受损的运动协调和共济失调。总之，我们得出结论，小脑颗粒神经元基本上需要适当水平的Wnt信号，以平衡其增殖和分化。
The Wnt/beta-catenin signaling pathway plays crucial roles in early hindbrain formation, and its constitutive activity is associated with a subset of human medulloblastoma, a malignant childhood tumor of the posterior fossa. However, the precise function of Wnt/beta-catenin signaling during cerebellar development is still elusive. We generated Math1-cre::Apc(Fl/Fl) mice with a conditional knockout for the Adenomatosis polyposis coli (Apc) gene that displayed a constitutive activity of Wnt/beta-catenin signaling in cerebellar granule neuron precursors. Such mice showed normal survival without any tumor formation but had a significantly smaller cerebellum with a complete disruption of its cortical histoarchitecture. The activation of the Wnt/beta-catenin signaling pathway resulted in a severely inhibited proliferation and premature differentiation of cerebellar granule neuron precursors in vitro and in vivo. Mutant mice hardly developed an internal granular layer, and layering of Purkinje neurons was disorganized. Clinically, these mice presented with significantly impaired motor coordination and ataxia. In summary, we conclude that cerebellar granule neurons essentially require appropriate levels of Wnt signaling to balance their proliferation and differentiation.