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- W73693504 abstract "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 centralnervous system, fails to close in the spinal region, and is a complex disorder with genetic andenvironmental components to its aetiology.Neural tube closure in the spinal region (spinal neurulation) involves bending of theneuroepithelium at the median hinge point (MHP) and dorsolateral hinge points (DLHPs)independently of the cytoskeleton. The MHP is redundant for spinal neurulation, but DLHPsare essential in the lumbosacral region. The Zic2 loss-of-function mouse mutant, Kumba,lacks DLHPs and genetically models spina bifida aperta resulting from this morphologicaldefect.The genes and pathways regulating DLHP formation are poorly understood. In thisthesis, the main molecular pathways driving DLHP formation were investigated. Antagonismof BMP signalling is necessary and sufficient to induce DLHPs. BMP antagonists were foundto be down-regulated in the Kumba spinal region, in conjunction with an up-regulation ofSmad-dependent and Smad-independent BMP signalling. Culture of whole Kumba embryoswith an inhibitor of Smad-dependent BMP signalling, dorsomorphin, induced DLHPs inKumba 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. Invitro assays showed that this gene is transcriptionally activated by Zic2, and Nr6a1-/- embryosdeveloped spinal neural tube defects.Excessive Shh signalling inhibits DLHP formation; however Zic2Ku/Ku;Shh-/- doublemutant mice developed spina bifida and lacked DLHPs. A defect in the Kumba notochordwas also characterised. Surprisingly, this did not disrupt neural tube patterning but maycontribute to a background-specific increase in ventral neuroepithelial proliferation. Inconclusion, Smad-dependent BMP signalling, but not the Shh pathway, regulates Zic2-mediated spinal neural tube morphogenesis." @default.
- W73693504 created "2016-06-24" @default.
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- W73693504 date "2012-04-28" @default.
- W73693504 modified "2023-09-27" @default.
- W73693504 title "The role of Zic2 in spinal neural tube morphogenesis" @default.
- W73693504 hasPublicationYear "2012" @default.
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