Over 250,000 pregnancies worldwide are affected by spina bifida each year, and the learning difficulties that limit many children’s independence stem from a poorly understood brain disorder called Chiari II, not just from the spinal defect itself. This matters because folic acid prevents fewer than half of spina bifida cases, and fetal surgery—while reducing hydrocephalus—does not protect against the higher brain defects that impair learning. The researchers have developed the first mouse model where spontaneous spina bifida leads to Chiari II brain defects, allowing them to test whether these defects arise secondarily from cerebrospinal fluid leaking through the open spine. They will examine how faulty neuron formation occurs in early embryos, use spatial transcriptomics to identify which molecular pathways are disrupted, and then attempt to prevent the brain anomalies by closing the spinal defect or trialling drugs in mouse embryos grown outside the mother’s body. If successful, this fundamental science could provide a proof-of-principle for preventing Chiari II brain defects in human pregnancies, potentially improving the cognitive outcomes for children born with spina bifida—especially those who undergo fetal surgery.
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Spina bifida (SB) is a common birth defect affecting annually over 250,000 pregnancies worldwide. Folic acid supplements reduce the SB rate but, even when added to the food supply (‘fortification’), folic acid prevents fewer than half of SB cases. With the growing availability of fetal surgery, more families are opting to have a live-born child with SB rather than abortion. However, the education and eventual independence of children with SB are limited not only by their lower body disability, but also by learning difficulties. These result from the Chiari II brain disorder which includes hydrocephalus and higher brain defects that affect learning. Fetal surgery for SB reduces hydrocephalus risk, but does not protect against the higher brain disorders. This research proposal aims to determine how the higher brain defects of Chiari II arise in embryos with SB. We are in a unique position to do this research, having recently developed the first mouse model in which spontaneous (genetic) SB leads to the higher brain defects of Chiari II. Our mouse has a genetically normal head, and so the presence of Chiari II brain defects demonstrates they arise secondary to the SB, potentially via leakage of cerebrospinal fluid from the open spinal cord. Our first results show that the higher brain defects result from faulty neuron production in the early embryo with SB. In Aim 1 of the proposal, we will examine the early stages of neuron formation in the brains of embryonic mice with SB, compared with normal littermates. We will identify whether a global disorder of neuron formation is present, or whether only certain neuron/glial types are affected. This information will reveal the fundamental basis of the Chiari II brain defects. In Aim 2, we will explore the underlying molecular basis of this disorder, using the contemporary method of ‘spatial transcriptomics’. This combines RNA sequencing (to identify which genes are expressed) with maintenance of the spatial structure of the tissue, in this case the brain. Hence, we aim to discover which genes are differently expressed in the various neuron-forming regions in brains of embryos with or without SB. This analysis will identify which of many molecular brain signalling pathways may be affected by the presence of SB, and which could be targets for novel therapies. In Aim 3, we will use mouse embryos that are grown outside the mother’s body. Using this system, we can close the SB at a much earlier stage than in human fetal surgery. This will test whether closure prevents the higher Chiari II brain disorder. Then we will trial drug treatments, at this same early stage, aimed at rectifying the disorders of neuron formation, and therefore preventing the brain anomalies. Overall, this project has the potential to significantly advance our understanding of the brain disorders in SB that affect so many children’s lives. Our prevention studies may form a proof-of-principle for subsequent studies in larger animals and, eventually, may benefit human pregnancies with SB, especially by improving the outcome for fetal surgery.
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