Impaired Embryonic Development in Mice Overexpressing the RNA-Binding Protein TIAR

Abstract

BackgroundTIA-1-related (TIAR) protein is a shuttling RNA-binding protein involved in several steps of RNA metabolism. While in the nucleus TIAR participates to alternative splicing events, in the cytoplasm TIAR acts as a translational repressor on specific transcripts such as those containing AU-Rich Elements (AREs). Due to its ability to assemble abortive pre-initiation complexes coalescing into cytoplasmic granules called stress granules, TIAR is also involved in the general translational arrest observed in cells exposed to environmental stress. However, the in vivo role of this protein has not been studied so far mainly due to severe embryonic lethality upon tiar invalidation.Methodology/Principal FindingsTo examine potential TIAR tissue-specificity in various cellular contexts, either embryonic or adult, we constructed a TIAR transgenic allele (loxPGFPloxPTIAR) allowing the conditional expression of TIAR protein upon Cre recombinase activity. Here, we report the role of TIAR during mouse embryogenesis. We observed that early TIAR overexpression led to low transgene transmission associated with embryonic lethality starting at early post-implantation stages. Interestingly, while pre-implantation steps evolved correctly in utero, in vitro cultured embryos were very sensitive to culture medium. Control and transgenic embryos developed equally well in the G2 medium, whereas culture in M16 medium led to the phosphorylation of eIF2α that accumulated in cytoplasmic granules precluding transgenic blastocyst hatching. Our results thus reveal a differential TIAR-mediated embryonic response following artificial or natural growth environment.Conclusions/SignificanceThis study reports the importance of the tightly balanced expression of the RNA-binding protein TIAR for normal embryonic development, thereby emphasizing the role of post-transcriptional regulations in early embryonic programming.

Encephalomyocarditis Virus Disrupts Stress Granules, the Critical Platform for Triggering Antiviral Innate Immune Responses

“…1). Constitutive aggregation of intrinsic SG components has been reported to lead to a severe stall in protein synthesis and eventual apoptosis (14,20). All the HeLa/G-G3BP clones displayed uniform and high-level GFP expression, and their growth rate was comparable to that of parental cells (our unpublished observations).…”

T-cell Intracellular Antigen (TIA)-Proteins Deficiency in Murine Embryonic Fibroblasts Alters Cell Cycle Progression and Induces Autophagy

“…Interestingly, a recent study has provided new evidence on the role of TIAR during mouse embryogenesis using an animal gain-of-function model. This report showed that TIAR controls embryo late pre-implantation stages and that its overexpression significantly impaired embryonic development beyond implantation, thereby revealing the requirement of tightly controlled TIAR expression levels for normal mouse embryo development [26]. The altered gene expression patterns associated to processes such as cell adhesion, differentiation, angiogenesis, apoptosis, proliferation and intracellular signal transduction suggest that TIA1 and TIAR play, individually and collectively, essential roles as master organizers of gene networks controlling embryonic outgrowth and patterning.…”

“…Further, these proteins seem to have an important role during embryogenesis. For example, mice lacking either TIA1 or TIAR, as well as ectopically over-expressing TIAR, show higher rates of embryonic lethality [18], [25], [26].…”

Stress puts TIA on TOP: Figure 1.

“…However, TIA-1 nullizygotes are fully fertile, whereas mice lacking the tiar gene are sterile (Beck et al 1998) due to a specific requirement for TIAR in primordial germ cell development and survival (Beck et al 1998). Moreover, overexpression of TIAR impairs embryonic development of mice at late preimplantation and post-implantation stages (Kharraz et al 2010), suggesting that balanced TIAR expression is absolutely required for early embryogenesis. The molecular mechanisms by which TIAR regulates these developmental processes are largely unknown.…”