Planar cell polarity signalling and mammalian neurulation

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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.