Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice
Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice
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DOI：
10.1172/jci35339
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发表时间：
2008-08-01
影响因子：
15.9
通讯作者：
Li, Xiao-Jiang
中科院分区：
文献类型：
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作者：
Sheng, Guoqing;Xu, Xingshun;Li, Xiao-Jiang
Joubert综合征是一种常染色体隐性遗传疾病，其特征是小脑和脑干的先天性畸形，并伴有脑内异常交叉。编码蛋白质AHI 1的Abelson辅助整合位点1基因的突变已被证明会导致朱伯特综合征。在这项研究中，我们发现小鼠Ahi 1与亨廷顿相关蛋白1（Hap 1）形成了一个稳定的复合物，这对新生儿发育至关重要，并参与细胞内运输。Hap 1基因敲除小鼠表现出Ahi 1水平显著降低、小脑发育缺陷和轴突交叉异常。抑制Ahi 1也降低了Hap 1的水平;截短的Ahi 1对应于joubert综合征的突变，抑制了神经元培养中的神经突生长。减少Hap 1表达抑制了TrkB的水平和内化，TrkB是一种介导神经发生和神经元分化的神经营养因子受体，这导致TrkB信号转导减少。这些发现提供了深入了解Joubert综合征的发病机制，并证明了Ahi 1-Hap 1复合物在早期脑发育中的关键作用。
Joubert syndrome is an autosomal recessive disorder characterized by congenital malformation of the cerebellum and brainstem, with abnormal decussation in the brain. Mutations in the Abelson helper integration site 1 gene, which encodes the protein AHI1, have been shown to cause joubert syndrome. In this study, we found that mouse Ahi1 formed a stable complex with huntingtin-associated protein 1 (Hap1), which is critical for neonatal development and involved in intracellular trafficking. Hap1-knockout mice showed significantly reduced Ahi1 levels, defective cerebellar development, and abnormal axonal decussation. Suppression of Ahi1 also decreased the level of Hap1; and truncated Ahi1, which corresponds to the mutations in joubert syndrome, inhibited neurite outgrowth in neuronal culture. Reducing Hap1 expression suppressed the level and internalization of TrkB, a neurotrophic factor receptor that mediates neurogenesis and neuronal differentiation, which led to decreased TrkB signaling. These findings provide insight into the pathogenesis of Joubert syndrome and demonstrate the critical role of the Ahi1-Hap1 complex in early brain development.