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Title: The role of putative Tbx1 traget genes in the pathogenesis of the 22q11 deletion syndrome phenotype
Author: Roberts, C.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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The 22q11 deletion syndrome (22q11DS/DiGeorge Syndrome [DGS]) is a congenital disorder with complex aetiology including cardiovascular, thymic/parathyroid, craniofacial and neuro-behavioural phenotypes. These arise via abnormal development of embryonic structures including the pharyngeal arch/artery apparatus and the secondary heart field. Large (3Mb) hemizygous deletions of 22q11containing the TBX1 transcription factor are found in most human cases. Animal models and non-deleted patient data suggest haploinsufficiency of TBX1 is the major underlying cause of 22q11DS. To investigate the role of Tbx1 in cardiovascular development, putative transcriptional targets were previously identified using microarray. This thesis examines the role of two such targets, the Cyp26 gene family and Hes1. These genes are known to be involved, respectively, in the retinoic acid (RA) and Notch-signalling pathways. Both pathways are important in pharyngeal/cardiovascular development. Control of RA homeostasis/dosage is required for normal development and the Cyp26 enzymes metabolise RA to less active forms. Embryonic Cyp26 genes have altered expression in Tbx1-/-mice. This project investigated the effect of chemically blocking Cyp26 function upon pharyngeal/cardiovascular development in the chick. Furthermore, a mutant mouse model was used to establish whether loss of Cyp26b1function could result in the 22q11DS phenocopy observed. Finally, epistasis experiments ascertained whether a genetic interaction exists between Tbx1 andCyp26b1. The transcriptional repressor Hes1 is required for normal pharyngeal/cardiovascular development in the mouse. This thesis presents data showing a conserved role for her6 (zebrafish homologue) in zebrafish pharyngeal development and verification of a tbx1/her6 genetic interaction during pharyngeal development. Overall, this work provides further evidence that Tbx1 co-ordinates a number of signalling pathways in pharyngeal/cardiovascular development. This data refines the role of Tbx1 and RA-regulatory genes in 22q11DS cardiovascular phenotypes and corroborates the importance of an interaction between tbx1 and her6 (Hes1) in pharyngeal development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available