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Title: The role of Zic2 in spinal neural tube morphogenesis
Author: Raza-Knight, S. R.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2012
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Spina bifida aperta is a common and disabling congenital defect, affecting 0.5- 2/1000 live births worldwide. It arises when the neural tube, precursor of the central nervous system, fails to close in the spinal region, and is a complex disorder with genetic and environmental components to its aetiology. Neural tube closure in the spinal region (spinal neurulation) involves bending of the neuroepithelium at the median hinge point (MHP) and dorsolateral hinge points (DLHPs) independently of the cytoskeleton. The MHP is redundant for spinal neurulation, but DLHPs are essential in the lumbosacral region. The Zic2 loss-of-function mouse mutant, Kumba, lacks DLHPs and genetically models spina bifida aperta resulting from this morphological defect. The genes and pathways regulating DLHP formation are poorly understood. In this thesis, the main molecular pathways driving DLHP formation were investigated. Antagonism of BMP signalling is necessary and sufficient to induce DLHPs. BMP antagonists were found to be down-regulated in the Kumba spinal region, in conjunction with an up-regulation of Smad-dependent and Smad-independent BMP signalling. Culture of whole Kumba embryos with an inhibitor of Smad-dependent BMP signalling, dorsomorphin, induced DLHPs in Kumba but failed to fully rescue the spina bifida. In addition, a known BMP repressor, Nr6a1, was identified as being downregulated in a microarray screen of the Kumba spinal region. In vitro assays showed that this gene is transcriptionally activated by Zic2, and Nr6a1-/- embryos developed spinal neural tube defects. Excessive Shh signalling inhibits DLHP formation; however Zic2Ku/Ku;Shh-/- double mutant mice developed spina bifida and lacked DLHPs. A defect in the Kumba notochord was also characterised. Surprisingly, this did not disrupt neural tube patterning but may contribute to a background-specific increase in ventral neuroepithelial proliferation. In conclusion, Smad-dependent BMP signalling, but not the Shh pathway, regulates Zic2- mediated spinal neural tube morphogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available