van Bueren, K.L.; (2008) Genomic and transcriptomic approaches to pathways affected in DiGeorge syndrome. Doctoral thesis , University of London.

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Abstract

This thesis describes the identification and characterisation of genes important in development of the pharyngeal apparatus and heart, the major structures affected in DiGeorge syndrome (DGS). DGS is characterised by craniofacial, cardiovascular, thymus and parathyroid defects. It is most commonly caused by heterozygous deletion of a 3Mb region of chromosome 22ql 1 encompassing at least 30 genes. Haploinsufficiency of the TBX1 transcription factor is considered to be the major underlying cause of this syndrome. Animal models of DiGeorge syndrome have demonstrated the importance of Tbxl in pharyngeal and heart development and therefore, identifying the downstream targets of Tbxl is of vital importance in understanding the development of these systems. This project was aimed at identifying cell autonomous effects of Tbxl by isolating Tbxl-lacZ expressing cells and comparing the gene expression profiles of Tbxl null and heterozygous cells by microarray analysis. Validation of the downregulated gene, Hesl has been further investigated by the characterisation of pharyngeal and heart defects in mice carrying null alleles of this potential Tbxl target. In addition, BAC recombineering was also conducted to generate a transgenic mouse carrying a GFP-labelled, reversible, mutant Tbxl allele. This modified Tbxl allele should provide the basis for further enrichment of Tbxl targets by allowing isolation of Tbxl-expressing cells from transgenic mice and subsequent restoration of Tbxl function by cre-mediated recombination. Furthermore, in order to identify other pathways important in heart development, DGS patients with atypical chromosome rearrangements were analysed. This approach led to the identification of a potentially disrupted gene, HIC2, whose function was analysed using gene trap mouse models and which was shown to play a role in heart development. Overall these experiments have led to the elucidation of novel genes and genetic pathways affected in DGS and have contributed to a better understanding of the mechanisms controlling morphogenesis of the pharyngeal apparatus and heart.

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