Selective neuronal requirement for huntingtin in the developing zebrafish
Selective neuronal requirement for huntingtin in the developing zebrafish
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DOI：
10.1093/hmg/ddp455
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发表时间：
2009-12-15
影响因子：
3.5
通讯作者：
Richards, Robert I.
中科院分区：
文献类型：
--
作者：
Henshall, Tanya L.;Tucker, Ben;Richards, Robert I.
亨廷顿氏病与其他八种神经退行性疾病有共同的分子基础，即现有的多聚谷氨酰胺束的扩展。在每种情况下，这种重复序列都发生在其他不相关的蛋白质中。这些蛋白质在大脑中表现出广泛和重叠的表达模式，但这些疾病的区别在于对突变最敏感的特定神经元子集的神经变性。因此，已经提出，这些基因中的多聚谷氨酰胺区域的扩增可能导致相应蛋白质的正常功能的扰动，并且这种扰动以某种方式有助于这些疾病的神经元特异性。因此，这些蛋白质的正常功能已成为研究的焦点，作为潜在的致病途径。我们已经使用合成的反义morpholinos抑制翻译的亨廷顿蛋白mRNA在早期斑马鱼的发展和以前报道的影响，亨廷顿蛋白减少铁转运和稳态。在这里，我们报告了亨廷顿蛋白功能丧失对发育中的神经系统的影响的分析，观察神经丘，嗅板和鳃弓的形态学的明显缺陷。这些缺陷的潜在共同起源进行了探讨，揭示受损的前基板和端脑的基因表达减少，对中脑或后脑的形成没有影响所示的神经板的最前区域的形成。这些调查表明，亨廷顿蛋白在端脑和基板前区域的形成中具有特定的“限速”作用，并且在特定的神经细胞类型中对亨廷顿蛋白功能的需求水平不同。
Huntington's disease shares a common molecular basis with eight other neurodegenerative diseases, expansion of an existing polyglutamine tract. In each case, this repeat tract occurs within otherwise unrelated proteins. These proteins show widespread and overlapping patterns of expression in the brain and yet the diseases are distinguished by neurodegeneration in a specific subset of neurons that are most sensitive to the mutation. It has therefore been proposed that expansion of the polyglutamine region in these genes may result in perturbation of the normal function of the respective proteins, and that this perturbation in some way contributes to the neuronal specificity of these diseases. The normal functions of these proteins have therefore become a focus for investigation as potential pathogenic pathways. We have used synthetic antisense morpholinos to inhibit the translation of huntingtin mRNA during early zebrafish development and have previously reported the effects of huntingtin reduction on iron transport and homeostasis. Here we report an analysis of the effects of huntingtin loss-of-function on the developing nervous system, observing distinct defects in morphology of neuromasts, olfactory placode and branchial arches. The potential common origins of these defects were explored, revealing impaired formation of the anterior-most region of the neural plate as indicated by reduced pre-placodal and telencephalic gene expression with no effect on mid- or hindbrain formation. These investigations demonstrate a specific 'rate-limiting' role for huntingtin in formation of the telencephalon and the pre-placodal region, and differing levels of requirement for huntingtin function in specific nerve cell types.