Nychyk, Oleksandr;
(2018)
The role of proteoglycans in the initiation of neural tube closure.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Neurulation is the embryonic process that gives rise to the neural tube (NT), the precursor of the brain and spinal cord. Recent work has emphasised the importance of proteoglycans in convergent extension movements and NT closure in lower vertebrates. The current study is focused on the role of proteoglycans in the initiation of NT closure in mammals, termed closure 1. In this project, the initial aim was to characterise the ‘matrisome’, or in vivo extracellular matrix (ECM) composition, during mammalian neurulation. Tissue site of mRNA expression and protein localisation of ECM components, including proteoglycans, were then investigated showing their distinct expression patterns prior to and after the onset of neural tube closure. The expression analysis raised various hypothesis that were subsequently tested, demonstrating that impaired sulfation of ECM proteoglycan chains worsens the phenotype of planar cell polarity (PCP) mutant loop tail (Vangl2Lp) predisposed to neural tube defects. Exposure of Vangl2Lp/+ embryos to chlorate, an inhibitor of glycosaminoglycan sulfation, during ex vivo whole embryo culture prevented NT closure, converting Vangl2Lp/+ to the mutant Vangl2Lp/Lp pathophenotype. The same result was obtained by exposure of Vangl2Lp/+ + embryos to chondroitinase or heparitinase. Taken together, it indicated that the PCP pathway functionally interacts with chondroitin and heparan sulfate proteoglycans during initiation of NT closure. In order to investigate the possible role of proteoglycans in mammalian convergent extension, the node of Vangl2Lp/+ embryos was labelled with DiO. The study revealed that the PCP-proteoglycan interaction is mediated independently of convergent extension. The failure of neural fold apposition and reduced Fgfr1 signalling was proposed as potential causative mechanism underlying failure of closure 1. In fish, the cilia motility is dependent on heparan sulfate chains, but this has not been studied in mammals. The present study identified a novel cellular localisation of cohesin/proteoglycan protein Smc3 and its GAG chains. Both Smc3 and CS-E are expressed in the midbody, primary and motile cilia. For the first time, this study showed the nuclear expression of CS chains in mouse embryo. The coordinated movement of Smc3 and CS-E chains during cytokinesis and ciliogenesis suggests conserved role of this protein in mouse cilia and cytokinetic apparatus.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of proteoglycans in the initiation of neural tube closure |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10046101 |
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