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Title: Circadian characterisation of the transcription factor Zfhx3 utilising a conditional mutagenesis approach
Author: Wilcox, Ashleigh G.
ISNI:       0000 0004 7966 348X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Previous work revealed an important role for the transcription factor ZFHX3 in circadian biology. A dominant missense mutation in the gene (Zfhx3Sci) results in a short circadian period in constant conditions and altered sleep homeostasis. However, constitutive knock-outs of this gene are embryonic lethal, limiting experimental characterisation options. In this thesis, the role of Zfhx3 in circadian rhythm regulation throughout the lifespan of the mouse is examined using conditional mutagenesis to produce Zfhx3 null animals. Inducible deletion of Zfhx3 in adult mice was achieved using a ubiquitously expressed inducible Cre line. These mice displayed significant circadian disruption, namely an acute shortening of circadian period and/or loss of rhythmicity in constant conditions. Following on from this, using SCN-enriched Cre lines driven by Six3 and Foxd1, Zfhx3 was deleted specifically in developing SCN. These animals showed a variety of sleep and circadian phenotypes when assessed. Homozygous mutants of the Six3-Cre line cross displayed a dramatic circadian phenotype; complete behavioural arrhythmia in all lighting conditions and an inability to entrain to a light-dark cycle. Histological examination revealed that the SCN in these mutants fails to mature, as evidenced by loss of expression of key circadian neuropeptides in this region. This work provides evidence for the sustained importance of Zfhx3 in circadian pacemaker function and highlights the use of conditional mutagenesis as an invaluable tool for the study circadian transcription factors. The data presented also suggests that Zfhx3 is crucial for development of the SCN in mice.
Supervisor: Nolan, Patrick ; Oliver, Peter ; Banks, Gareth Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available