Characterisation of a forkhead transcription factor, FOXE1

FOXE1, a forkhead transcription factor, plays an essential role in the development of the thyroid and hair follicle. Loss-of-function FOXE1 mutations cause aberrant morphogenesis of both tissues, apparently due to a defect in cell migration. In the mature thyroid, FOXE1 plays an essential role in the control of thyroid hormone synthesis, modulating both thyroglobulin and thyroid peroxidase gene expression. Several studies have shown there is considerable inter-individual variability in thyroid hormone levels, and this is due at least in part to genetic factors. One of the main features of the FOXE1 protein is a highly polymorphic polyalanine tract that can range in size from 11 to 19-Ala residues (wild-type being 14-Ala residues). The aims of this thesis were: 1) To determine the precise location of FOXE1 expression within the human hair follicle. 2) To identify genes involved in cell migration that could be potential FOXE1 target genes. 3) To investigate the possible role of FOXE1 polyalanine polymorphisms in thyroid dysfunction. 1) Immunohistochemical analysis confirmed previous observations that FOXE1 was expressed in human epidermis and hair follicle outer root sheath. However, technical difficulties prevented more detailed analyses (e.g. colocalisation with hair-specific proteins). 2) Bioinformatics yielded several potential FOXE1 target genes. Subsequent QPCR-based expression profiling and siRNA-based gene knockdown experiments suggested TIMP3 as a likely direct downstream target. Thus, FOXE1 may have a direct role in the modulation of ECM architecture by migratory cells. 3) The genotyping of a small cohort of subclinical hypothyroid subjects, showed there to be an increased incidence of the 16-Ala allele compared with the control group. Luciferase assays revealed the transcriptional activity of the 16-Ala allele to be significantly reduced compared with wild-type. This provides the first evidence that polymorphic variation can affect the transcriptional activity of FOXE1, and be a possible contributing factor in the sub-optimal thyroid function.EThOS - Electronic Theses Online ServiceGBUnited Kingdo