Contribution of the co-chaperone STI1 in mouse development: embryonic stem cell as approach

Abstract

Stress inducible protein 1 was originally identified as a co-chaperone able to modulate heat shock protein (Hsp) activities. In fact, several evidence suggest that STI1 is not only an adapter protein to link Hsps. The interaction of STI1 with various partners such as Hsp family members, transcription factors, prion protein (PrPC) among others, demonstrates its functional versatility. Several cellular localization of STI1 indicate that this protein could participate in the formation of multiprotein complexes in the nucleus, cytoplasm and/or extracellular milieu, with distinct biological activities. Interestingly, when at the extracellular space, the soluble form of STI1 is able to interact with PrPC, a cell surface glycoprotein, and orchestrates relevant biological phenomena related to nervous system development and neural plasticity, such as self-renewal of neural progenitors, control of neural differentiation and survival, and memory consolidation. Recent findings show STI1 involved in the regulation of pluripotency status of embryonic stem cells, suggesting a role for STI1 during embryogenesis. Given those data that demonstrate several biological functions associated to STI1, and in attempt to explore the role of STI1 in mammalian development, a constitutive knockout mouse, deficient for STI1 gene, was generated. Preliminary data show that in homozygous knockout animals, the STI1 deletion is lethal and leads to embryo degeneration which seems to occur between E6.5 and E10.5, indicating that STI1 could play an essential role during mammalian development. Hence, the culture of pluripotent embryonic stem cells, become an approach more adequate to study the mechanism involved in the lethality observed in STI1 knockout embryos during early development. Regarding that little is known about the contribution of STI1 to maintenance of embryonic stem cells and embryo development, and based on literature data that show the key role for STI1 in events that govern the brain plasticity during the development, the main goal of this proposal is to investigate the role of STI1 in the embryo development using embryonic stem cell as a model and evaluate the role of its main partner, PrPC, in these processes. (AU)