Pozzi, S; (2017) The role of HESX1 (Hesx1) in mouse embryonic stem cell fate maintenance and pre-implantation development. Doctoral thesis , UCL (University College London).

Abstract

Hesx1 is a homeobox transcriptional repressor that is required for correct specification and development of the forebrain and pituitary gland. Moreover, inactivating mutations in humans have been previously linked with Septo Optic Dysplasia (SOD), a congenital condition causative of hypopituitarism and optic-nerve hypoplasia. Although Hesx1 was initially isolated from embryonic stem cells (ESC) almost two decades ago, its role in stemness remains mostly unknown. In this thesis I aim to elucidate the role of Hesx1 in the maintenance of ESC fate, with particular focus on the connection between this transcription factor and the complex network regulating ESC pluripotency. I show that the core pluripotency network composed by OCT4, SOX2 and NANOG directly interact with the Hesx1 promoter modulating its expression. Molecular studies indicate that Hesx1 is a target of the JAK/STAT signalling in response to LIF stimulation. Analysis of newly generated Hesx1 deficient ESC demonstrates that, in the absence of Hesx1, ESC undergo molecular profile changes, which renders them prone to lineage differentiation, possibly because of a defect in their response to LIF signalling. I also show that Hesx1 is expressed in the pre-implantation embryo, where I hypothesise may play a role in maintenance of diapause. Finally, I describe the identification of a novel HESX1 mutation in a paediatric case of SOD, and demonstrate its detrimental effect on protein function. All together, my data suggest that Hesx1 has a conserved function in the maintenance of pluripotency in both ESC and the pre-implantation embryo.

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