Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation.
Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation.
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Ahi1 缺失会损害 BM88/Cend1 介导的神经元分化，从而影响早期发育
DOI：
10.1523/jneurosci.0119-13.2013
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发表时间：
2013-05-08
期刊：
影响因子：
--
通讯作者：
Li XJ
中科院分区：
文献类型：
--
作者：
Weng L;Lin YF;Li AL;Wang CE;Yan S;Sun M;Gaertig MA;Mitha N;Kosaka J;Wakabayashi T;Xu X;Tang B;Li S;Li XJ
Abelson辅助整合位点-1（AHI 1）基因突变导致N-末端Ahi 1片段并导致Joubert综合征，这是一种与发育延迟相关的常染色体隐性脑畸形疾病。AHI 1突变如何导致发育延迟仍不清楚。在这里，我们报告说，全长，但不是N-末端，Ahi 1结合Hap 1，亨廷顿蛋白相关的蛋白，是必不可少的小鼠的出生后的生存，这种结合在神经元分化的神经生长因子调节。神经生长因子诱导Hap 1A的去磷酸化，并减少其与Ahi 1的关联，与Hap 1A在神经突尖端的分布增加相关。因此，Ahi 1与磷酸化的Hap 1A在胞质中，但不是在突触体，从小鼠脑中分离的组分，表明Ahi 1的功能主要在神经元的索马。细胞溶质Ahi 1免疫沉淀物的质谱分析显示，Ahi 1还结合Cend 1（细胞周期退出和神经元分化蛋白1）/BM 88，一种介导神经元分化的神经元蛋白，在出生后小鼠脑中高度表达。Ahi 1基因敲除小鼠的下丘脑中Cend 1的水平降低，这表明在出生后几天生长迟缓。过量表达Ahi 1可以稳定培养细胞中的Cend 1。此外，Cend 1的过表达可以挽救Ahi 1基因敲除小鼠下丘脑神经元突起延伸缺陷。我们的研究结果表明，Cend 1是参与Ahi 1相关的下丘脑神经元分化的早期发展，让我们新的见解Joubert综合征延迟发展背后的机制。
Mutations in the Abelson helper integration site-1 (AHI1) gene result in N-terminal Ahi1 fragments and cause Joubert syndrome, an autosomal recessive brain malformation disorder associated with delayed development. How AHI1 mutations lead to delayed development remains unclear. Here we report that full-length, but not N-terminal, Ahi1 binds Hap1, a huntingtin-associated protein that is essential for the postnatal survival of mice and that this binding is regulated during neuronal differentiation by nerve growth factor. Nerve growth factor induces dephosphorylation of Hap1A and decreases its association with Ahi1, correlating with increased Hap1A distribution in neurite tips. Consistently, Ahi1 associates with phosphorylated Hap1A in cytosolic, but not in synaptosomal, fractions isolated from mouse brain, suggesting that Ahi1 functions mainly in the soma of neurons. Mass spectrometry analysis of cytosolic Ahi1 immunoprecipitates reveals that Ahi1 also binds Cend1 (cell cycle exit and neuronal differentiation protein 1)/BM88, a neuronal protein that mediates neuronal differentiation and is highly expressed in postnatal mouse brain. Loss of Ahi1 reduces the levels of Cend1 in the hypothalamus of Ahi1 KO mice, which show retarded growth during postnatal days. Overexpressed Ahi1 can stabilize Cend1 in cultured cells. Furthermore, overexpression of Cend1 can rescue the neurite extension defects of hypothalamic neurons from Ahi1 KO mice. Our findings suggest that Cend1 is involved in Ahi1-associated hypothalamic neuronal differentiation in early development, giving us fresh insight into the mechanism behind the delayed development in Joubert syndrome.