Failure of neural tube closure in the loop-tail (Lp) mutant mouse: analysis of the embryonic mechanism
Failure of neural tube closure in the loop-tail (Lp) mutant mouse: analysis of the embryonic mechanism
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DOI：
10.1016/s0165-3806(97)00099-0
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发表时间：
1997-09-20
期刊：
影响因子：
--
通讯作者：
Copp, AJ
中科院分区：
文献类型：
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作者：
Gerrelli, D;Copp, AJ
环尾 (Lp) 在小鼠突变体中是独一无二的，它无法在 5-7 体节阶段启动颈/后脑边界的神经管闭合（所谓的“闭合 1”）。 Lp/Lp 胚胎继续发育出一种与颅轴劈裂非常相似的畸形，这是人类发现的最严重的神经管缺陷。我们研究了 Lp 神经管闭合失败的几种可能的胚胎学机制。使用聚合酶链式反应扩增与 Lp 密切相关的多态性微卫星序列，鉴定了来自混合窝的 Lp/Lp、Lp/+ 和 +/+ 胚胎的基因型。在神经形成后的发育阶段，Lp/Lp 胚胎的体轴缩短，这可能表明轴伸长缺陷是 Lp 的主要异常。然而，我们发现在有缺陷的Closure 1阶段之前，Lp纯合子的轴伸长是正常的，这表明后期胚胎的体轴缩短是神经异常的继发效应，或者是Lp突变的独立效应。一些工作人员报告说，晚期 Lp/Lp 胚胎的细胞增殖率异常。我们观察到胚胎组织之间以及不同体节阶段的胚胎之间[H-3]胸苷标记指数和有丝分裂指数的变化。然而，Lp/Lp、Lp/+ 和 +/+ 胚胎具有非常相似的细胞增殖参数，反对基于错误胚胎生长的机制。第三，我们测试了这样的假设，即环尾缺陷是由于神经褶皱无法并列造成的，特别是在闭合 1 的位置。通过在胚胎轴周围，在闭合 1 的未来位置，我们能够实现神经褶皱在该位置的收敛。然而，在缝合的 Lp/Lp 胚胎中，神经折叠闭合未能沿着体轴进展，而与手术后的 Lp/+ 和 +/+ 胚胎相比，后者表现出神经管闭合的正常进展。因此，环尾的胚胎缺陷似乎涉及脊柱神经褶皱普遍无法沿着脊柱区域并列，或者涉及神经褶皱融合过程中的缺陷。 (C) 1997 Elsevier Science B.V.
Loop-tail (Lp) is unique among mouse mutants in failing to initiate neural tube closure at the cervical/hindbrain boundary (so-called 'Closure 1'), at the 5-7 somite stage. Lp/Lp embryos go on to develop a malformation that closely resembles cranio-rachischisis, the most severe neural tube defect found in humans. We investigated, several possible embryological mechanisms that may underlie this failure of neural tube closure in Lp. The genotypes of Lp/Lp, Lp/+ and +/+ embryos from mixed Litters were identified using the polymerase chain reaction to amplify a polymorphic microsatellite sequence that is very closely linked to Lp. At post-neurulation stages of development, Lp/Lp embryos have a shortened body axis, which could suggest a, defect of axial elongation as the primary anomaly in Lp. However, we found that axial elongation is normal in Lp homozygotes prior to the stage of defective Closure 1, indicating that the shortened body axis of later embryos is a secondary effect of the neurulation anomaly, or an independent effect of the Lp mutation. Some workers have reported cell proliferation rates to be abnormal in later stage Lp/Lp embryos. We observed variations in [H-3]thymidine labelling index, and mitotic index, between embryonic tissues, and between embryos at different somite stages. However, Lp/Lp, Lp/+ and +/+ embryos had closely similar cell proliferation parameters, arguing against a mechanism based on faulty embryonic growth. Thirdly, we tested the hypothesis that the defect in loop-tail results from an inability of the neural folds to become apposed, specifically at the site of Closure 1. By tying a silk suture around the embryonic axis, at the future site of Closure 1, we were able to effect convergence of the neural folds at this site. Neural fold closure failed to progress along the body axis in sutured Lp/Lp embryos, however, in contrast to operated Lp/+ and +/+ embryos which exhibited normal progression of neural tube closure. The embryonic defect in loop-tail appears, therefore, to involve either a general inability of the spinal neu al folds to become apposed along the spinal region, or a defect in the process of neural fold fusion. (C) 1997 Elsevier Science B.V.