Sajedi, E; (2008) Role of the homeobox HESX1/HESX1 in forebrain and pituitary development in mouse and human. Doctoral thesis , UCL (University College London).

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Abstract

The homeobox gene Hesx1 encodes a transcriptional repressor that is required, within the anterior neural plate of the vertebrate embryo, for normal forebrain and pituitary development. Hesx1'' mice display variable defects, affecting midline telencephalic commissural tracts, the eyes and the pituitary gland. In humans, mutations in HESX1 are associated with hypopituitarism and septo-optic dysplasia (SOD), a condition characterised by pituitary abnormalities in association with midline telencephalic structure and optic nerve defects. In this thesis, a dual approach was used, in order to gain insights into HESX1 function. Firstly, a yeast two-hybrid screen identified DNMT1, LONP2, SRFBP1, SAFB1 and ZFP592 as protein partners of HESX1. Mapping of the interacting regions indicated that different domains of HESX1 are involved in each of these interactions. The five proteins co-localise with HESX1 in the nucleus and their transcripts are co-expressed with Hesxl in mouse embryos. Furthermore, these interactions are disrupted by various HESX1 mutations. The binding with DNMT1 was characterised in more detail, since this protein has a crucial role in gene silencing through its DNA methylation properties. Thus this interaction suggests a novel mechanism for the repressing activity of HESX1. Secondly, gene targeting was used to generate two knock-in mouse models, based on two autosomal recessive human HESX1 mutations, I26T and R160C. I26T has been associated with anterior pituitary hypoplasia in a patient, whilst R160C was identified in two siblings with SOD. Hesxl embryos display fully penetrant pituitary defects with frequent occurrence of eye abnormalities, whereas the telencephalon develops normally. HesxlR160C/R160C embryos display more severe forebrain and pituitary defects that are identical to those observed in Hesxl' ' mice. These data indicate that Hesxl-I26T is a hypomorphic allele, whereas Hesxl-R160C yields a null allele and consequently causes a more severe phenotype in mice and humans.

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