Zohn Irene E
Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
Birth Defects Res C Embryo Today. 2012 Jun;96(2):193-205. doi: 10.1002/bdrc.21011.
Neural tube defects (NTDs) such as spina bifida and anencephaly are some of the most common structural birth defects found in humans. These defects occur due to failures of neurulation, a process where the flat neural plate rolls into a tube. In spite of their prevalence, the causes of NTDs are poorly understood. The multifactorial threshold model best describes the pattern of inheritance of NTDs where multiple undefined gene variants interact with environmental factors to cause an NTD. To date, mouse models have implicated a multitude of genes as required for neurulation, providing a mechanistic understanding of the cellular and molecular pathways that control neurulation. However, the majority of these mouse models exhibit NTDs with a Mendelian pattern of inheritance. Still, many examples of multifactorial inheritance have been demonstrated in mouse models of NTDs. These include null and hypomorphic alleles of neurulation genes that interact in a complex fashion with other genetic mutations or environmental factors to cause NTDs. These models have implicated several genes and pathways for testing as candidates for the genetic basis of NTDs in humans, resulting in identification of putative pathogenic mutations in some patients. Mouse models also provide an experimental paradigm to gain a mechanistic understanding of the environmental factors that influence NTD occurrence, such as folic acid and maternal diabetes, and have led to the discovery of additional preventative nutritional supplements such as inositol. This review provides examples of how multifactorial inheritance of NTDs can be modeled in the mouse.
神经管缺陷（如脊柱裂和无脑畸形）是人类中发现的一些最常见的结构出生缺陷。这些缺陷是由于神经胚形成失败导致的，神经胚形成是一个扁平神经板卷成神经管的过程。尽管神经管缺陷很常见，但其病因却知之甚少。多因素阈值模型最能描述神经管缺陷的遗传模式，即多个未定义的基因变异与环境因素相互作用导致神经管缺陷。迄今为止，小鼠模型已表明许多基因是神经胚形成所必需的，这为控制神经胚形成的细胞和分子途径提供了机制上的理解。然而，这些小鼠模型中的大多数表现出孟德尔遗传模式的神经管缺陷。尽管如此，在神经管缺陷的小鼠模型中已经证明了许多多因素遗传的例子。这些包括神经胚形成基因的无效和低表达等位基因，它们以复杂的方式与其他基因突变或环境因素相互作用导致神经管缺陷。这些模型已经暗示了几个基因和途径作为人类神经管缺陷遗传基础测试的候选者，从而在一些患者中鉴定出了推定的致病突变。小鼠模型还提供了一个实验范式，以获得对影响神经管缺陷发生的环境因素（如叶酸和母体糖尿病）的机制理解，并导致发现了其他预防性营养补充剂，如肌醇。本综述提供了神经管缺陷多因素遗传如何在小鼠中建模的例子。
