Planar cell polarity signalling and mammalian neurulation

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。然而，如果母亲在怀孕前和怀孕早期服用叶酸补充剂，受影响怀孕的风险可以大大降低。不幸的是，并非所有NTD病例都可以通过叶酸预防，而且似乎要在预防NTD方面取得进一步进展，需要更深入地了解缺陷的根本原因（遗传和环境）。最近的研究揭示了几种基因，当它们在小鼠中发生突变时，会阻止神经管闭合的最初步骤，导致严重的脊柱裂。值得注意的是，这些基因似乎都参与了相同的生化途径，称为平面细胞极性途径，这似乎是早期胚胎细胞协调运动所必需的。在这个项目中，我们将专注于这些基因，以确定它们在发育中的小鼠胚胎中的特定功能，并了解这对神经管的形成至关重要。虽然这些发育研究将在小鼠模型中进行，但我们最近发现一些患有严重脊柱裂的人也携带平面细胞极性基因的改变。我们计划通过在小鼠中测试相同突变的影响来测试这些改变（或突变）是否是NTD患者脊柱裂的原因。身份证明？风险？基因将提供一个机会，提供遗传咨询的夫妇谁影响怀孕，并将是一个关键的一步，发展新的个性化疗法，以预防NTD。

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. However, the risk of an affected pregnancy can be substantially reduced if the mother takes folic acid supplements before and during early pregnancy. Unfortunately, not all cases of NTDs are preventable by folic acid and it seems that to make further progress in prevention of NTDs will require a deeper understanding of the underlying causes of the defects (both genetic and environmental). Recent studies have revealed several genes, which when mutated in mice, prevent the initial step of neural tube closure, resulting in severe spina bifida. Significantly, these genes all seem to be involved in the same biochemical pathway, called the planar cell polarity pathway, which appears to be needed for co-ordinated movement of cells in the early embryo. In this project we will focus on these genes, to determine their specific function in the developing mouse embryo, and to understand how this is essential for the neural tube to form. Although these developmental studies will be carried out in mouse models, we have recently found that some humans with severe spina bifida also carry alterations in planar cell polarity genes. We plan to test whether these alterations (or mutations) are responsible for spina bifida in patients with NTDs, by testing the effect of the same mutation in mice. Identification of ?risk? genes will provide an opportunity to offer genetic counselling to couples who have affected pregnancies, and will be a key step towards developing new personalised therapies for prevention of NTDs.