Palmer, AJ; (2015) Cellular and molecular mechanisms underlying Pax3-related neural tube defects. Doctoral thesis , UCL (University College London).

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Abstract

The neural tube is the developmental precursor of the central nervous system (CNS). Neural tube defects (NTDs) are among the commonest birth defects, affecting approximately 1 in 1000 pregnancies. They occur when the neural tube fails to close completely during neurulation, and result in an open region of the CNS. Spina bifida is an NTD affecting the spinal region, and it can lead to lifelong disability, including incontinence, motor difficulties, and paralysis below the level of the lesion. Exencephaly is an NTD affecting the cranial region, and is not compatible with life. Splotch mice carry a mutation in the Pax3 gene which leads to a functionally null Pax3 protein. Pax3 is important in the development of a number of tissues, and mutant embryos have defects in muscle development, and neural crest-derived tissues, such as the heart, peripheral nervous system and melanocytes. Additionally, embryos develop NTDs; they demonstrate spina bifida with complete penetrance and exencephaly with partial penetrance. The cellular mechanism behind the development of NTDs in Splotch embryos is not well understood. However excess apoptosis, premature neuronal differentiation, and reduced proliferation in the neural tube have all been proposed as potential causes. Furthermore, research has suggested a potential link between Pax3 and canonical Wnt signalling. The aim of this research was to study cellular defects in Splotch mice which are potentially causative of NTDs, and also to study the interaction between Pax3 and canonical Wnt signalling. It was found that excess apoptosis and premature neuronal differentiation are not causative of spina bifida in Splotch mice. However, reduced proliferation is present in the neural tube, and may be causative. Additionally, β-catenin loss- and gain-of-function mutations were used to study interaction between Pax3 and canonical Wnt signalling. β-catenin loss-of-function reduces Pax3 expression, and β-catenin gain-of-function worsens NTDs in Pax3 mutant embryos, whereas loss-of-function partially rescues exencephaly, but not spina bifida, in these embryos. β-catenin gain- and loss-of-function both also worsen neural crest defects in Pax3 mutant embryos. Therefore, Canonical Wnt signalling interacts with Pax3 during development, and affects the cranial and spinal regions of the neural tube differently. In summary, Pax3 mutation results in a number of defects in developing embryos, including NTDs and neural crest defects. Cellular processes have been studied in this research to identify abnormalities which could be causative of these defects, and a potential molecular link between Pax3 and the canonical Wnt signalling pathway has been identified, which could contribute to the observed phenotype.

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