Abstract 20358: The mRNA Binding Protein Zfp36l1 Regulates Cardiac Development Genes and is Essential for Cardiac Function in Adulthood

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Abstract

Introduction: Several key transcription factors are known to orchestrate the majority of cardiac morphogenesis during embryonic development. However, the post-transcriptional regulation of these essential genes has not been well described. Zfp36L1 is a tandem zinc finger protein that binds to AU-rich elements (AREs) in the 3’ untranslated region (UTR) of mRNA transcripts and promotes their degradation. Global knock-out (KO) of Zfp36L1 in mice results in lethality at embryonic day 11 (E11). However, a subset of these mice developed additional cardiac structural abnormalities including myocardial thinning. To determine the requirement for Zfp36L1 in cardiac development, we generated cardiac specific Zfp36L1 KO mice. We hypothesize that Zfp36L1 fine-tunes the canonical gene expression programs during cardiac development, and its deletion will result in cardiomyopathy due to deficits in cardiac differentiation.

Results: Unbiased gene ontology analysis of an RNA immunoprecipitation-sequencing dataset using Zfp36L1 as bait in mouse embryonic stem cells revealed significant enrichment for genes involved in cardiac cell fate specification, and included master regulators such as Nkx2.5 and Isl1. To delete Zfp36L1 during cardiac development, we generated Zfp36L1f/f mice bearing the Mlc2a-Cre transgene (cs-Zfp36L1 KO), which results in excision beginning at E8. cs-Zfp36L1 KO mice were born in Mendelian ratios and displayed normal systolic function at 8 weeks of age as assessed by echocardiography. However, thinning of the myocardial wall and expansion of the left ventricle was observed as early as 11 weeks and progressed through 24 weeks of age. Additionally, histological analysis revealed thinning of the RV wall and an enlarged RV chamber. Heart weight to tibia length ratio in cs-Zfp36L1 KO mice also increased compared to wild type littermates, suggesting a mixed hypertrophy and dilation phenotype.

Conclusion: Although cardiac-specific deletion of Zfp36L1 in embryonic development did not result in profound structural defects, mice developed progressive cardiac dysfunction after birth. This finding highlights the critical role of Zfp36L1 in fine-tuning the cardiac development program to ensure normal cardiac function later in life.

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