Grainyhead-like genes and mammalian neural tube defects

粒头样基因和哺乳动物神经管缺陷

• 批准号: G0802163/1
• 负责人: Nicholas Greene
• 金额: $ 80.26万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0802163%2F1
• 关键词: Grainyhead; like; genes; mammalian; neural

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.

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。神经管未能正确形成导致一组称为神经管缺陷（NTD）的出生缺陷，其中胎儿的大脑和/或脊髓受到不可逆的损伤，导致出生前或出生后不久死亡，或存活婴儿的残疾。总体而言，NTD发生率约为1/1，000，尽管发生率各不相同，并且在某些地区（例如北方爱尔兰和苏格兰）明显更高。在全球范围内，每年约有13万例病例发生。NTD的风险取决于遗传遗传因素和非遗传因素，如饮食，但确切的原因还不清楚。我们正在研究易于发展类似于相应人类出生缺陷的NTD的小鼠品系，目的是了解缺陷发展的原因并找到预防方法。在其中一个菌株中，卷曲尾，我们发现一种叫做grainyhead-like-3的基因表达减少，导致NTD。我们现在有证据表明，相同基因或相关基因grainyhead-like-2的表达增加也会导致NTD，我们建议使用遗传学方法来验证这一想法。然后，我们将研究如何改变grainyhead样基因的表达改变细胞行为，从而改变发育胚胎的机械性能，使神经管无法关闭。最后，我们将测试是否grainyhead样-2和-3的失调导致NTDs通过类似或不同的影响，其他？下游？基因.在小鼠中导致NTD的基因的鉴定可能指示可能在人类中致病的基因。对人类NTD基因的了解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。