Grainyhead-like genes and mammalian neural tube defects

在怀孕早期，胚胎发育中的一个关键事件是神经管的形成，神经管随后将发育成大脑和脊髓。神经管不能正确形成会导致一组被称为神经管缺陷（神经管缺陷）的出生缺陷，其中胎儿的大脑和/或脊髓受到不可逆转的损伤，导致出生前或出后不久死亡，或对存活的婴儿造成障碍。总的来说，被忽视的热带病发生率约为千分之一，尽管这一比率有所不同，在某些区域（如北爱尔兰和苏格兰）要高得多。在世界范围内，每年大约发生13万例病例。被忽视热带病的风险取决于遗传因素和非遗传因素，如饮食，但确切的原因尚不清楚。我们正在研究易患ntd的小鼠品系，这些品系类似于相应的人类出生缺陷，目的是了解缺陷产生的原因并找到预防方法。在其中一种菌株，卷尾菌株中，我们发现一种被称为颗粒状-3的基因表达减少，导致了ntd。我们现在有证据表明，同一基因或相关基因（似粒头-2）的表达增加也会导致NTDs，我们建议使用遗传学方法来验证这一观点。然后，我们将研究颗粒状基因表达的改变如何改变细胞行为，从而改变发育中的胚胎的机械特性，使神经管无法闭合。最后，我们将测试样粒头2和样粒头3的失调是否通过对其他下游基因表达的相似或不同的影响而导致NTDs。基因。在小鼠中引起NTDs的基因鉴定可能提示在人类中可能引起NTDs的基因。了解导致人类被忽视热带病的基因，可以为考虑进一步怀孕的受影响家庭提供更准确的咨询，并可以开发新的治疗策略。

During early pregnancy, a crucial event in the developing embryo is the formation of the neural tube, which will later develop into the brain and spinal cord. Failure of the neural tube to form correctly leads to a group of birth defects called neural tube defects (NTDs), in which the brain and/or spinal cord of the fetus become irreversibly damaged, resulting in death before or shortly after birth, or handicap in surviving babies. Overall, NTDs occur in around 1 per 1,000 pregnancies although the rate varies and is significantly higher in some regions (e.g. Northern Ireland and Scotland). Worldwide, approximately 130,000 cases occur every year. The risk of NTDs depends on both inherited genetic factors and non-genetic factors such as diet, but the exact causes are not well understood. We are studying mouse strains that are predisposed to develop NTDs that resemble the corresponding human birth defects, with the aim of understanding why the defects develop and finding ways to prevent them. In one of these strains, curly tail, we found that reduced expression of a gene called grainyhead-like-3, causes NTDs. We now have evidence to suggest that increased expression of the same gene or a related gene, grainyhead-like-2, can also cause NTDs, and we propose to use genetic approaches to test this idea. We will then investigate how the altered expression of the grainyhead-like genes changes cellular behaviours and thereby alters the mechanical properties of the developing embryo such that the neural tube fails to close. Finally, we will test whether dysregulation of grainyhead-like-2 and -3 cause NTDs through similar or differing effects on the expression of other ?downstream? genes. Identification of the genes that cause NTDs in mice may indicate genes that may be causative in humans. Knowledge of the genes responsible for NTDs in humans may then allow more accurate counselling for affected families who are considering a further pregnancy, and may allow development of novel therapeutic strategies.