Mouse models for neural tube closure defects
Mouse models for neural tube closure defects
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DOI：
10.1093/hmg/9.6.993
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发表时间：
2000-01-01
影响因子：
3.5
通讯作者：
Harris, MJ
中科院分区：
文献类型：
--
作者：
Juriloff, DM;Harris, MJ
神经管闭合缺陷（NTD），特别是无脑畸形和脊柱裂，是常见的人类出生缺陷（1/1000），其遗传学是复杂的，其风险降低围受孕期母体叶酸补充。有>60种小鼠突变体和品系具有NTD，许多是在过去2年中报道的。NTD突变不仅在基因座上具有广泛的功能异质性，而且大多数突变体表现出可变的低多态性，有些突变体表现出复杂的遗传模式（例如SELH/Bc，Abl/Arg，Mena/Profilin 1）。在大多数这些小鼠模型中，NTD是露脑畸形（相当于无脑畸形）或脊柱裂或两者兼而有之，反映了在明确定义的、机械上不同的隆起区中神经褶隆起的失败。NTD风险在各种模型中通过不同的母体营养补充剂降低，包括叶酸（Pax 3，Cart 1，Cd突变体），肌醇（ct）和蛋氨酸（Axd）。胚胎中缺乏从头甲基化（Dnmt 3b-null）会导致NTD风险，我们建议在几种模型中甲基化与观察到的颅NTD中女性过量之间存在潜在联系。一些令人惊讶的NTD突变体（Gadd 45 a，Terc，Trp 53）表明，具有基本有丝分裂功能的基因也具有神经折叠升高的特异性功能。在几种小鼠NTD模型中突变的基因涉及肌动蛋白调节（Abl/Arg、Macs、Mena/Profilin 1、Mlp、Shrm、Vcl），支持肌动蛋白在神经褶升高中的假定关键作用，并且可能是寻找人类NTD基因的良好候选途径。
Neural tube closure defects (NTDs), in particular anencephaly and spina bifida, are common human birth defects (1 in 1000), their genetics is complex and their risk is reduced by periconceptional maternal folio acid supplementation. There are >60 mouse mutants and strains with NTDs, many reported within the past 2 years. Not only are NTD mutations at loci widely heterogeneous in function, but also most of the mutants demonstrate variable low penetrance and some show complex inheritance patterns (e.g. SELH/Bc, Abl/Arg, Mena/ Profilin1). In most of these mouse models, the NTDs are exencephaly (equivalent to anencephaly) or spina bifida or both, reflecting failure of neural fold elevation in well defined, mechanistically distinct elevation zones. NTD risk is reduced in various models by different maternal nutrient supplements, including folic acid (Pax3,Cart1, Cd mutants), inositol (ct) and methionine (Axd). Lack of de novo methylation in embryos (Dnmt3b-null) leads to NTD risk, and we suggest a potential link between methylation and the observed female excess among cranial NTDs in several models. Some surprising NTD mutants (Gadd45a, Terc, Trp53) suggest that genes with a basic mitotic function also have a function specific to neural fold elevation. The genes mutated in several mouse NTD models involve actin regulation (Abl/Arg, Macs, Mena/Profilin1, Mlp, Shrm, Vcl), support the postulated key role of actin in neural fold elevation, and may be a good candidate pathway to search for human NTD genes.