Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse
Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse
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DOI：
10.1093/hmg/ddg014
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发表时间：
2003-01-15
影响因子：
3.5
通讯作者：
Copp, AJ
中科院分区：
文献类型：
--
作者：
Murdoch, JN;Henderson, DJ;Copp, AJ
Circletail 是仅有的两种表现出最严重神经管缺陷（NTD）（称为颅骨劈裂）的小鼠突变体之一。在这种疾病中，由于神经管闭合失败，几乎整个大脑和脊髓都受到影响。颅骨劈裂是导致人类死亡的一个重要原因，但所涉及的分子机制仍知之甚少。在这里，我们报告了使用定位克隆方法鉴定了circletail（Crc）突变基因。该基因 Scrb1 编码与果蝇 scribble 相关的 LAP 蛋白家族成员，具有 16 个富含亮氨酸的重复序列和 4 个 PDZ 结构域。 Crc 突变体包含一个单碱基插入，该插入会产生移码并导致 Scrb1 蛋白过早终止。我们报告了胚胎和胎儿发育过程中 Scrb1 的表达模式，并表明 Scrb1 表达密切反映了 Crc/Crc 突变体中观察到的表型缺陷。此外，circletail与loop-tail突变体存在遗传相互作用，我们揭示了Scrb1与Vangl2（loop-tail突变基因）的重叠表达。 Crc 基因的鉴定进一步定义了启动神经管闭合所需的遗传途径的性质，并提供了可能与人类 NTD 病因学有关的重要新候选基因。
Circletail is one of only two mouse mutants that exhibit the most severe form of neural tube defect (NTD), termed craniorachischisis. In this disorder, almost the entire brain and spinal cord is affected, owing to a failure to initiate neural tube closure. Craniorachischisis is a significant cause of lethality in humans, yet the molecular mechanisms involved remain poorly understood. Here, we report the identification of the gene mutated in circletail (Crc), using a positional cloning approach. This gene, Scrb1, encodes a member of the LAP protein family related to Drosophila scribble, with 16 leucine rich repeats and four PDZ domains. The Crc mutant contains a single base insertion that creates a frame shift and leads to premature termination of the Scrb1 protein. We report the expression pattern of Scrb1 during embryonic and fetal development, and show that Scrb1 expression closely mirrors the phenotypic defects observed in Crc/Crc mutants. In addition, circletail genetically interacts with the loop-tail mutant, and we reveal overlapping expression of Scrb1 with Vangl2, the gene mutated in loop-tail. The identification of the Crc gene further defines the nature of the genetic pathway required for the initiation of neural tube closure and provides an important new candidate that may be implicated in the aetiology of human NTDs.