Grainyhead-like genes and mammalian neural tube defects

在怀孕早期，发育中的胚胎中的一个关键事件是神经管的形成，神经管随后将发育到大脑和脊髓。神经管未能正确形成会导致一组称为神经管缺陷(NTDS)的出生缺陷，在这种缺陷中，胎儿的大脑和/或脊髓会受到不可逆转的损害，导致出生前或出生后不久死亡，或使存活的婴儿残疾。总体而言，每1,000名孕妇中约有1名发生NTDS，尽管比率各有不同，在一些地区(如北爱尔兰和苏格兰)明显更高。在世界范围内，每年大约发生13万起病例。NTDS的风险既取决于遗传因素，也取决于非遗传因素，如饮食，但确切原因尚不清楚。我们正在研究容易患上类似于相应人类出生缺陷的NTDS的小鼠品系，目的是了解这些缺陷发生的原因，并找到预防它们的方法。在其中一种名为Curly Tail的菌株中，我们发现一种名为Grainyhead-like-3的基因表达减少会导致NTDS。我们现在有证据表明，相同基因或相关基因--谷头样蛋白-2的表达增加也会导致NTDS，我们建议使用遗传学方法来测试这一观点。然后，我们将研究颗粒状基因的表达变化如何改变细胞行为，从而改变发育中的胚胎的机械性能，从而使神经管无法关闭。最后，我们将测试颗粒头样蛋白-2和-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。识别导致老鼠NTDS的基因可能表明可能导致人类NTDS的基因。了解导致人类NTDS的基因可能会为考虑再次怀孕的受影响家庭提供更准确的咨询，并可能开发新的治疗策略。

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.