The translation initiation factor homolog eif4e1c regulates cardiomyocyte metabolism and proliferation during heart regeneration

Abstract

The eIF4E family of translation initiation factors bind 5’ methylated caps and act as the limiting-step for mRNA translation. The canonical eIF4E1A is required for cell viability, yet other related eIF4E families exist and are utilized in specific contexts or tissues. Here, we describe a family called Eif4e1c for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but is lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution forms an interface along the protein surface, suggesting Eif4e1c functions in a novel pathway. Deletion of eif4e1c in zebrafish caused growth deficits and impaired survival in juveniles. Mutants surviving to adulthood had fewer cardiomyocytes and reduced proliferative responses to cardiac injury. Ribosome profiling of mutant hearts demonstrated changes in translation efficiency of mRNA for genes known to regulate cardiomyocyte proliferation. Although eif4e1c is broadly expressed, its disruption had most notable impact on the heart and at juvenile stages. Our findings reveal context-dependent requirements for translation initiation regulators during heart regeneration.

Harnessing the regenerative potential ofinterleukin11to enhance heart repair

“…scRNA-seq analysis of uninjured and regenerating hearts was done as described in 82 . Briefly, we obtained count files from GSE159032 and GSE158919 44 and reanalyzed with Seurat package 83 .…”

“…The 50 principal components (PCs) of the PCA with resolution 4 were used for clustering. Marker genes to identify cell-types are listed in 82 .…”