The function of Smad-interacting factors in neuroectoderm differentiation of human embryonic stem cells

To further understand the molecular mechanisms involving Activin/Nodal signalling in pluripotency, I studied in hESCs the function of two Smad-binding partners, Smad-Interacting Protein 1 (SIP1) and Ectodermin, which are involved in neuroectoderm specification in amphibians and in the mouse. This report demonstrates that Activin/Nodal signalling cooperates with NANOG, OCT4 and SOX2 to tightly control the expression of the SIP1 in hESCs. In turn, SIP1 plays a role in pluripotency by limiting the positive effect of Activin/Nodal signalling on mesendoderm differentiation. Importantly, SIP1 favours neuroectoderm differentiation and protects neuroectodermal cells from the mesoderm-inducing effect of BMP signalling, confirming that SIP1 has a key function in this early cell fate decisions. Similar results were obtained with pluripotent stem cells derived from post-implantation mouse embryos (mEpiSCs) implying that these mechanisms are evolutionarily conserved and suggesting that they could take place in vivo during early development of mammalian embryos. My study on the function of SIP1 explains the mechanisms by which Activin/Nodal signalling and SIP1 regulate the cell fate decision between neuroectoderm and mesendoderm in the progression from pluripotency to primary germ later differentiation. I present my preliminary studies on the function of Ectodermin in hESCs, and I propose that Ectodermin does not play a role in neuroectoderm differentiation, but may be involved in mesendoderm differentiation. Finally, I provide some preliminary results on understanding the function of SMAD4 in hESCs, and propose that the classical effectors of Activin/Nodal signalling, that is, SMAD2, SMAD3 and SMAD4, may have differential roles in propagating Activin/Nodal signalling effects.EThOS - Electronic Theses Online ServiceGBUnited Kingdo