Grainyhead-like genes and mammalian neural tube defects

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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. 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.