Genetic interaction between members of the Vangl family causes neural tube defects in mice
Genetic interaction between members of the Vangl family causes neural tube defects in mice
复制标题
DOI：
10.1073/pnas.0712126105
复制
发表时间：
2008-03-04
影响因子：
11.1
通讯作者：
Gros, Philippe
中科院分区：
文献类型：
--
作者：
Torban, Elena;Patenaude, Anne-Marie;Gros, Philippe
神经管缺陷是人类常见的先天性畸形。最近，我们已经记录了与NTDs的独立关联的Vangl1和Vangl2基因突变。在环尾小鼠中，VANGL1的功能缺失等位基因的纯合性（而不是杂合性）导致严重的NTD颅裂，而在散发性和家族性病例的人类队列中，VANGL1突变变体的杂合性与NTD有关。为了了解Vangl1在正常发育中的作用，我们创建了一个在Vangl1上具有失活突变的小鼠突变体（Vangl1(gt)）。在神经管闭合时，Vangl1在发育中的神经管和脊索中呈现动态表达模式。尽管Vangl1（gt/gt）在耳蜗内毛细胞极性上有细微的变化，但其杂合子和纯合子都是可育的。值得注意的是，与健康的Vangl1（gt/+）和Vangl2（lp/+）杂合子相反，Vangl1(gt/+)；Vangl2（lp/+）双杂合子表现出严重的发育缺陷，包括严重的颅裂、内耳缺陷（Corti器官毛细胞的立体纤毛束紊乱）和心脏异常（右锁骨下动脉异常）。这些结果表明，Vangl1（gt/+）和Vangl2（lp/+）基因之间的遗传相互作用导致神经管缺陷，并提出了单个Vangl基因与其他遗传位点和/或环境因素之间的相互作用可能也有助于ntd的病因学。
Neural tube defects (NTDs) are very frequent congenital abnormalities in humans. Recently, we have documented independent association of Vangl1 and Vangl2 gene mutations with NTDs. In the Looptail mouse, homozygosity (but not heterozygosity) for loss-of-function alleles at Vangl2 causes the severe NTD craniorachischisis, whereas heterozygosity for mutant variants of VANGL1 is associated with NTDs in a human cohort of sporadic and familial cases. To understand the role of Vangl1 in normal development, we created a mouse mutant with an inactivating mutation at Vangl1 (Vangl1(gt)). Vangl1 shows a dynamic pattern of expression in the developing neural tube and notochord at the time of neural tube closure. Vangl1(gt/+) heterozygotes and Vangl1(gt/gt) homozygotes are viable and fertile, although Vangl1(gt/gt) display subtle alterations in polarity of inner hair cells of the cochlea. Remarkably, and as opposed to healthy Vangl1(gt/+) and Vangl2(lp/+) heterozygotes, Vangl1(gt/+);Vangl2(lp/+) double heterozygotes show profound developmental defects that include severe craniorachischisis, inner ear defects (disorganization of the stereociliary bundles of hair cells of the organ of Corti), and cardiac abnormality (aberrant right subclavian artery). These results show that genetic interaction between Vangl1(gt/+) and Vangl2(lp/+) genes causes neural tube defects and raise the possibility that interaction between individual Vangl genes and other genetic loci and/or environmental factors may additionally contribute to the etiology of NTDs.