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Title: Characterisation of hitchhiker, a novel mouse mutant with spina bifida
Author: Patterson, Victoria Louise
ISNI:       0000 0004 2722 2383
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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Neural tube defects are a set of developmental malformations which can be highly debilitating, with limited treatment available. Mouse mutants exhibiting neural tube defects are studied to identify processes promoting proper neural tube closure, and potential points of intervention for future therapies. This thesis characterises the mouse mutant hitchhiker (hhkr), a hypomorphic allele of Tulp3 which presents with neural tube defects and polydactyly. The spina bifida and exencephaly observed in hhkr mutants are demonstrated to be consequences of failure of neural tube closure, and excessive proliferation is identified in the hindbrain neuroepithelium of mutant embryos. Intriguingly, increases apoptosis was reported for the Tulp3tmlJng mutant (lkeda et aI., 2001), and this increase is not conserved in Tulp3hhkr. Further support is provided for the role of Tulp3 as a negative regulator of Sonic hedgehog (Shh) signalling, confirming such a role in the limb, while preliminary data from genetic interaction studies between hhkr and Tectonic-/- are presented to suggest Tulp3 may exert a positive influence on Shh signalling in cranial regions. The molecular function of the Tulp3 protein is investigated, revealing an interaction between Tulp3 and Alx1, a transcription factor involved in skeletal patterning. An interaction between Tulp3 and Trim71, an E3 ubiquitin ligase is also demonstrated and supported by the eo- localisation of the proteins in transfected cells. Tulp3 is shown to be ubiquitinated in vivo, although this modification does not appear to be dependent on Trim7!. This thesis provides evidence that Tulp3 is likely to be involved in diverse protein-protein interactions around the cell, and some of these interactions may be crucial in promoting the proper closure of the neural tube.
Supervisor: Murdoch, Jenny ; Begbie, Jo Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Spina bifida ; Neural tube--Abnormalities