The Translation Initiation Factor Homolog, eif4e1c, Regulates Cardiomyocyte Metabolism and Proliferation During Heart Regeneration

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 new family called Eif4e1c that is ancestral to the canonical eIF4E1A in vertebrates, and for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but has been lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution from ray-finned fish to sharks forms an evolutionarily conserved binding interface along the surface of the protein, 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, while also showing 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 expressed in many tissues and is the predominant cap-binding initiation homolog in embryos, 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. Significance Statement Studies of gene expression during regeneration have focused on the abundance of mRNA transcripts. Here, we describe how translation is regulated to promote proliferation of cardiomyocytes during development and regeneration in zebrafish. The canonical cap binding protein, EIF4E1A, recognizes mRNA and stimulates ribosomes loading. Aquatic vertebrates have an ortholog called Eif4e1c that is lost in terrestrial vertebrates. Zebrafish mutants in eif4e1c have growth and survival deficits with smaller hearts, associated with reduced proliferation of cardiac muscle. They also display diminished cardiomyocyte cycling after injury. Dysregulation of translation in mutant hearts likely underlies these phenotypes. Identification of the novel ortholog eif4e1c as a factor in proliferation of cardiomyocytes is an unexpected finding with implications for how translation can stimulate heart repair.