Investigating genetic factors underlying hypopituitarism and septo-optic dysplasia in humans

Differentiation of pituitary progenitors into the six different hormone-producing cell types that form the mature organ is a complex process that requires the coordinated spatial and temporal expression of multiple genes. Over the past decades, it has become apparent that mutations in a number of these developmentally important pituitary-specific transcription factors, including Hesx1 and Sox2, leads to hypopituitarism with or without syndromic features such as septo-optic dysplasia (SOD). This thesis extends previous work in further understanding basic pituitary development with the ultimate goal of increasing knowledge of hypopituitarism and SOD in humans. Hesx1 was one of the first genes implicated in these conditions. It is a homeobox transcriptional repressor that is required for normal anterior forebrain and pituitary development in mouse and human. Here a dual approach was used to advance our understanding of Hesx1 function in the developing hypothalamic-pituitary axis (HPA). Firstly, phenotypic analysis of the neuroendocrine hypothalamus in Hesx1 mouse models has revealed an original role for Hesx1 in the development of this structure, providing a strong correlation with human SOD cases. Secondly, functional analysis of novel HESX1 mutations has showed that mutations occurring within the homeodomain impede DNA binding whilst repressor activity is maintained, providing more insight into the molecular function of HESX1. Sox2 is a SOXB1-HMG-box transcription factor that has been recently associated with hypopituitarism, demonstrating a requirement of SOX2 for normal HPA development and function in humans. We used a condition approach in mice to investigate the pathogenesis of these defects. Our observations demonstrate that Sox2 is required for the normal proliferation of pituitary progenitors, and for the terminal differentiation of the Pit1 lineage. Furthermore, Hesx1Cre/+;Sox2fl/fl embryos exhibit reduced GnRH neurogenesis, providing insights into the characteristic hypogonadotrophic hypogonadism observed in SOX2 patients. Combined, the Hesx1Cre/+;Sox2fl/fl mouse provides a suitable model for understanding the pathogenesis of SOX2 mutations in humans