Canonical mRNA cap binding proteins have distinct roles in regeneration from the fish specific ortholog eif4e1c
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Date
2025-05
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The Ohio State University
Abstract
Zebrafish are valuable models for cardiac regeneration due to their remarkable ability to regenerate heart tissue. Our research focuses on the eIF4E family of translation initiation factors, which are suspected to play a role in this process. While canonical eIF4E is found in all terrestrial vertebrates and is essential for cell viability, zebrafish also contain an additional ortholog that is unique to aquatic vertebrates, called eif4e1c. Previously, we showed that deletion of eif4e1c impaired growth, survival, and heart regeneration. It is unclear whether these phenotypes result from the reduced total level of cap-binding proteins-or if eif4e1c has specialized functions. To investigate further, we used CRISPR to make zebrafish deletion mutants for canonical eif4ea and eif4eb. Concurrent deletion of eif4e1c and eif4ea resulted in a further mortality and size deficits when compared to the solo eif4e1c mutants. Compound mutants of eif4e1c and eif4eb found similar growth defects, but no exacerbation of mortality. The eIF4E family of translation initiation factors are required for viability in eukaryotes from yeast to mice. Surprisingly, deletion of both eif4ea and eif4eb did not result in any obvious phenotypic changes in survival, growth, nor heart size. However, it was found that the loss of canonical eif4ea or eif4eb alone results in improved cardiomyocyte regeneration, and impaired fin regeneration. Compound mutants of a canonical and eif4e1c lose these regeneration phenotypes suggesting a “goldilocks” threshold where eif4e1c begins to compensate fully for the loss of canonical factors. This is to say, there may be a required ratio – canonical factors to eif4e1c – which allows for compensation. These results suggest eif4e1c can fully compensate for the loss of the canonical EIF4E factors, while the canonical factors only partially compensate for the loss of eif4e1c. This suggests that the fish specific eif4e1c ortholog is a bona fide translation initiation factor with additional functions that impact growth and survival.
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Keywords
Translation, Eif4e1c, Initiation Factor, Regeneration, Blastema