Poster abstracts
Poster number 44 submitted by Anupama Rao
Translation Initiation Factor Eif4e1c Drives Cardiac Growth During Development and Regeneration in Zebrafish
Anupama Rao (Molecular, Cellular, and Developmental Biology), Ishrat Jahan (Department of Biological Chemistry and Pharmacology, The Ohio State University), Baken Lyu (Department of Biological Chemistry and Pharmacology, The Ohio State University), Kenneth Poss (Department of Cell Biology, Duke University ), Kedryn Baskin (Department of Cell Biology and Physiology, The Ohio State University), Joseph Aaron Goldman (Department of Biological Chemistry and Pharmacology, The Ohio State University)
Abstract:
The mammalian heart lacks the capacity to regenerate damaged tissues making heart disease the leading cause of death in the world. However, zebrafish can regenerate large portions of cardiac tissues lost following injury. Many studies have investigated transcriptional changes occurring during regeneration to identify molecules and pathways driving this process. Here, we show that translation initiation factor, eif4e1c is required for efficient zebrafish heart development and regeneration. The eIF4E family of translation initiation factors bind 5’ methylated caps and act as rate limiting factors to determine mRNA translation. Deletion of eif4e1c in zebrafish using CRISPR resulted in lower survival rates to adulthood and overall growth deficits. Adult hearts had fewer cardiomyocytes (CMs) in eif4e1c mutants and CM proliferation was impaired during regeneration. Previous studies have hypothesized lower mitochondrial activity to be pro-proliferative. Surprisingly, we found that mitochondria in uninjured eif4e1c mutant hearts have lower activity even though CM proliferation is impaired in development. Lower mitochondrial activity was also observed in regenerating wildtype hearts in line with previous literature. Taken together, mitochondrial respiration appears to have both, pro-growth and inhibitory effects on heart muscle depending on context and the developmental stage. In conclusion, our study supports a model of cardiac regeneration in which translation is a critical component of regulating gene expression to drive CM proliferation.
References:
1. Poss, K.D., Wilson, L.G., and Keating, M.T. (2002). Heart Regeneration in Zebrafish. Science 298, 2188–2190.
2. Meyer, K.D., Patil, D.P., Zhou, J., Zinoviev, A., Skabkin, M.A., Elemento, O., Pestova, T.V., Qian, S.-B., and Jaffrey, S.R. (2015). 5’ UTR m(6)A Promotes Cap-Independent Translation. Cell 163, 999 1010.
3. Leppek, K., Das, R., and Barna, M. (2017). Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat Rev Mol Cell Bio 19, 158 174.
4. Hinnebusch, A.G., Ivanov, I.P., and Sonenberg, N. (2016). Translational control by 5’-untranslated regions of eukaryotic mRNAs. Science 352, 1413 1416.
5. Liu, Y., Beyer, A., and Aebersold, R. (2016). On the Dependency of Cellular Protein Levels on mRNA Abundance. Cell 165, 535–550.
Keywords: Cardiac regeneration, Translation, Zebrafish