Planar cell polarity signalling and mammalian neurulation

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。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，并不是所有的NTDS病例都可以通过叶酸预防，似乎在预防NTDS方面取得进一步进展需要对缺陷的根本原因(遗传和环境)有更深入的了解。最近的研究揭示了几个基因，当这些基因在老鼠身上发生突变时，可以阻止神经管关闭的初始步骤，从而导致严重的脊柱裂。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，这似乎是早期胚胎中细胞协调运动所必需的。在这个项目中，我们将重点研究这些基因，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是如何必不可少的。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类也携带平面细胞极性基因的变化。我们计划通过在小鼠身上测试相同突变的效果，来测试这些变化(或突变)是否与NTDS患者的脊柱裂有关。风险的识别？基因将为影响怀孕的夫妇提供遗传咨询的机会，并将是开发预防NTDS的新的个性化疗法的关键一步。

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.