Shh Signaling Protects Atoh1 from Degradation Mediated by the E3 Ubiquitin Ligase Huwe1 in Neural Precursors
Shh Signaling Protects Atoh1 from Degradation Mediated by the E3 Ubiquitin Ligase Huwe1 in Neural Precursors
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DOI：
10.1016/j.devcel.2014.05.014
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发表时间：
2014-06-23
影响因子：
11.8
通讯作者：
Ayrault, Olivier
中科院分区：
文献类型：
--
作者：
Forget, Antoine;Bihannic, Laure;Ayrault, Olivier
由音刺猬 (SHH) 和转录因子 Atoh1 控制的信号网络调节小脑颗粒神经元祖细胞 (GNP) 的增殖和分化。这些发育过程的失调会导致髓母细胞瘤的形成，这是儿童时期最常见的恶性脑肿瘤。尽管 Atoh1 蛋白是小脑发育和髓母细胞瘤形成过程中的关键因素，但其功能和调节的最新详细机制仍知之甚少。在此，我们报道 SHH 通过防止 E3 泛素连接酶 Huwe1 的磷酸依赖性降解来调节 Atoh1 的稳定性。我们的结果表明，SHH 和 Atoh1 有助于促进神经元前体扩张的正向自动调节循环。因此，小鼠 SHH 髓母细胞瘤中 Huwe1 的缺失说明了癌症中这种发育机制的破坏。因此，小脑发育过程中 SHH 信号传导和 Atoh1 之间的串扰凸显了一个可以进一步针对髓母细胞瘤的协作网络。
Signaling networks controlled by Sonic hedgehog (SHH) and the transcription factor Atoh1 regulate the proliferation and differentiation of cerebellar granule neuron progenitors (GNPs). Deregulations in those developmental processes lead to medulloblastoma formation, the most common malignant brain tumor in childhood. Although the protein Atoh1 is a key factor during both cerebellar development and medulloblastoma formation, up-to-date detailed mechanisms underlying its function and regulation have remained poorly understood. Here, we report that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1. Our results reveal that SHH and Atoh1 contribute to a positive autoregulatory loop promoting neuronal precursor expansion. Consequently, Huwe1 loss in mouse SHH medulloblastoma illustrates the disruption of this developmental mechanism in cancer. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in medulloblastoma.